MCGOVERN MEDICAL SCHOOL’S BROWN FOUNDATION INSTITUTE of MOLECULAR MEDICINE FOR THE PREVENTION of HUMAN DISEASES IMMpact Report

FISCAL YEAR 2019 About the cover

A butterfly garden is a new addition to the courtyard of McGovern Medical School’s Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases.

IMMpact Report is published by McGovern Medical School. All correspondence should be addressed to: Office of Communications 6431 Fannin, B.340 Houston, TX 77030 E-mail: [email protected]

Articles and photos may be reprinted with permission.

Editor Darla Brown, Director, Office of Communications

Contributors: Darla Brown IMM Faculty Roman Petrowski

Design: Roy Prichard

Photography: Dwight Andrews

For information on supporting programs at the McGovern Medical School and the IMM, contact Lise Cameron, 713.500.3602, [email protected]

OOC-AbsoluteColor-1125-3/20 The University of Texas Health Science Center at Houston (UTHealth) Leadership Giuseppe N. Colasurdo, MD President Kevin Dillon, MBA, CPA Senior Executive Vice President, Chief Operating & Financial Officer Michael Blackburn, PhD Executive Vice President, Chief Academic Officer Barbara J. Stoll, MD Dean, McGovern Medical School

IMM Senior Administrator John F. Hancock, MA, MB, BChir, PhD, ScD, MRCP(UK), FRACP Executive Director

IMM Advisory Council Members John McDonald, Chair Alan Baden David Beck John Beckworth Louana Frois Theodore Frois Irma Gigli, MD Steven Gordon John F. Hancock, MA, MB, BChir, PhD, ScD, MRCP(UK), FRACP John Mackel Rodney Margolis Brad McWilliams Dudley Oldham Charles Parker Judy Perkins Beth Robertson Shavonnah Roberts Schreiber Ralph Thomas

The University of Texas System Board of Regents Kevin P. Eltife, Chairman Janiece Longoria, Vice Chairman James C. “Rad” Weaver, Vice Chairman David J. Beck Christina Melton Crain Daniel R. Dominguez R. Steven Hicks Jodie Lee Jiles Nolan Perez Kelcy L. Warren IMMPACT REPORT 1 • • • • 8 on a 14 12 The Bovay Translating Foundation – Foundation Shining a light Shining neglected system Building Bridges Building research in the lab research

6 10 mysteries of mysteries Unlocking the Unlocking eating disorders of cancer treatment A vision for the future Features Director's Message Director's Locations Our Genetics Center for Cardiovascular Genetics Center for Human Diseases and Autoimmune Center for Immunology Diseases and Degenerative Center for Metabolic Imaging Center for Molecular Biomedicine Center for Precision Medicine Cell and Regenerative Center for Stem Institute Therapeutics Texas IMM Service Centers the Numbers By Report Gift

Contents 2 3 Mission 4 16 19 25 30 39 45 52 68 77 79 81 • 2 IMMPACT REPORT 2 1 Director’s Message benefit from discovery. this goalofpatient specifically toachieve Therapeutics Institute talent inthe Texas IMM hasorganized solutions. The medical IMM focusesonthese benefit ofpatients. The of discovery andtothe therapies arederivative New diagnosticsand to newsolutions. defects. Discoveries lead caused bysinglegene problems thatarenot are unsolvedmedical cardiovascular diseases cancer, Alzheimer’s,and since diabetes,obesity, is amajorchallenge, the IMMfaculty. This highest priorityfor Discovery isthe objectives: two major The IMMhas I John S.Dunn Distinguished University ChairinPhysiology andMedicine Executive Director, Institute ofMolecular Medicine John Hancock, MA,MB,BChir, PhD, ScD date inyour calendarbecauseitisagreat tovisittheIMM. opportunity have allyour questionsanswered. Full detailsare inthisreport; pleasemark the to discussitsimplicationsforthe future of medicineandhealthcare, andto excellent tohearexciting opportunity research storiesdirectly from ourfaculty, evening. As inpreviousluminating andentertaining years thesymposiumisan and treatment, you willneedtocomethesymposium.It il- willbeavery IMM researchers are attheforefront ofthisemergingfieldcancer research cancer. If you wanttohermore technologyandhow aboutthisstate-of-the-art atIMMtodevelop highly specifictherapeuticstotarget of uniqueexpertise is designedtohelpcancerresearchers from allaround Texas takeadvantage and colleaguesinthe Texas Therapeutics Institute atIMM.The CPRITgrant Research Institute of Texas thatwasawarded (CPRIT) toDr. ZhiqiangAn toshowcasein part $6Mgrantfrom amajornew theCancer Prevention and talks onusingantibodiestofightcancer. We chosethisnovel andexciting topic attended areception intheJames T. Willerson, M.D.Discovery Hall. year, 145guestslistenedtotwotalksintheBeth Robertson Auditorium and tively, Iwouldbedelightedtoseeyou at ourannualIMMsymposium.Last can alsobeinvolved, Iwouldbepleasedtotalkwithyou personally. Alterna- growth anddevelopment oftheIMM.If you wouldliketo investigate how you council,whichplaysakeyrole inthecontinued cation oftheIMMadvisory disease. In thisregard, we are deeplyappreciative ofthestrong work anddedi- of ourmissiontotranslatemoleculardiscoveries therapiesfor human intonew develop ourrelationships withallinourcommunitywhovalue theaspiration generosity ofourfriendsanddonors. collaborations,and,mostimportantly,foundations, industry thecontinuing from alternativeattracting support sources, includingresearch charitiesand That said,fullimplementationofourmission remains heavilydependenton in attractingresearch fundsfrom whatisanever-diminishing nationalpool. able qualityandcreativity ofourscientiststhattheIMMremains so successful grant fundingforeachofthelastseven years! It isatestament totheremark- over theprioryear. Indeed, we have now substantiallyincreased ourextramural again over the preceding year, whichinturnhadseenaconsiderableincrease again. Over thefinancialgrantsandcontracts year justended,ournew were up challenging, especiallyfrom theNIH.Despite this,IMMfacultyhave excelled from eachIMMfacultymemberdescribingtheirresearch programs. onsomeofourfacultyanddonorsplusanaccount will findin-deptharticles tists whocollaboratecloselywithourclinicalcolleagues.Inside thereport you tients. To thisend,we have teamsofoutstandingbasicandtranslationalscien- translational outcomesfrom research inmolecularmedicinethatbenefitspa- embedded withinMcGovern Medical School.TheIMMmissionistodeliver This year thesymposiumwillbeheld April 29,2020,andwillfeature two In additiontoadvancing scienceandmedicine,we therefore wishto The environment forscientific research fundingcontinuestobeextremely man Diseases (IMM).TheIMMisastand-alone research institutethatis Foundation Institute ofMolecular Medicine forthePrevention ofHu- ’m pleasedtointroduce thelatestannualIMMpactreport forThe Brown IMMPACT REPORT 3 • • • • As an institute of McGovern As an institute of McGovern to medical practice are of to medical practice are major importance to product in biotechnology development and the pharmaceutical the IMM has industry, to the potential and desire form important and links its collaborations between activities and research own industries to apply its various and intellectual discoveries properties to pharmaceutical opportunities. School, the Brown Medical of Institute Foundation for the Medicine Molecular Diseases of Human Prevention to set the example strives and excellence for research nationally, collaboration locally, and internationally. However, it is clear that it is clear However, the applications Because research and the future practice and the future research novel of medicine with more therapies. These approaches been most successfully have used to determine the causes of and genetic infectious disorders diseases. molecular and cell biology in will play a major role clarifying the causes of many of modern problems unsolved medicine, such as heart disease, hypertension, vascular major mental disorders, illnesses, and inflammatory and immunologic diseases. of the institute’s research The is inspiring and investigators to fulfill the mission promises of the IMM. of molecular and cell biology

he Brown Foundation Foundation he Brown of Molecular Institute for the Medicine

Advances in molecular and Advances Mission

Prevention of Human Diseases Diseases of Human Prevention institute (IMM) is a research the that seeks to investigate causes of human diseases at the cellular and molecular using DNA and protein levels, technologies to elucidate disease mechanisms. This development of particular are and progress planning for future interest important in the increasingly The of clinical research. area to design institute endeavors methods of rational therapy possible, and, wherever of strategies for the prevention human diseases. enormous cell biology have medical potential for innovative T • 4 IMMPACT REPORT at St. Luke’s Episcopal Hospital The Denton A.Cooley Building – Texas Heart Institute South CampusResearch Building –3(SCRB3) Fayez S.Sarofim Research Building Our Locations • • • • • • • • Located inthe Texas Medical Center. tech laboratory. The IMMoccupiesa31,000square-foot high- Cyclotron, offices. wet labs,andsupport Imaging, Optical Imaging Tracers, a Emission Tomography, Magnetic Resonance Opened in 2009,thisfacilityhousesPositron South Campusofthe Texas Medical Center. Six-stories, 315,000square-feet locatedonthe GE Healthcare andthe Texas Enterprise Fund. Center andUTHealth, incooperationwith University of Texas MDAndersonCancer SCRB3 isacollaborationbetween The 255,748 gross square feet. Opened in2006,thebuildingencompasses the Texas Medical Center. (UTHealth) University Center Tower within Texas Health ScienceCenteratHouston Located adjacenttotheThe University of staff. administration, andsupport Primary homeoftheIMM’s faculty, IMMPACT REPORT 5 • • • • SAVE THE DATE SAVE Fayez S. Sarofim Research Building S. Fayez 1825 Pressler Street Kendra Carmon, PhD Kendra Assistant Professor Cancer Translational IMM Center for Research Attacking colorectal Attacking cancer stem cells with weaponized antibodies

Kyoji Tsuchikama, PhD Kyoji Assistant Professor Therapeutics Institute Texas Drug payloads and Drug payloads designer antibodies: homing to build How anti-cancer missiles

The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases the Prevention Institute of Molecular Medicine for Foundation The Brown Arming antibodies: A new strategy to fight cancer to strategy A new Arming antibodies: Wednesday, April 29, 2020 Wednesday, 4:00 - 6:30 pm IMMpact Symposium IMMpact • 6

IMMPACT REPORT Profiles in research “ T are co-regulated by neurons that haviors inobesityandanorexia idea isthatdefective feedingbe- defective,” Dr. Tong says. “Our ropathways inthebrainthatare identify keyneurons andneu- regulate feedingbehaviorand the brainpathwaysthatcan brain. inthe toms maybestarting helping patientswhosesymp- Tong isspecificallyinterested in to specialdietsorexercise, Dr. ishment. However, inaddition causing anorexia andmalnour- focuses ontherefusal toeat obesity, whiletheotherend looks atover-eating leadingto of feedingbehavior. One side both extremes ofthespectrum family.”fects almostevery society,” Dr. Tong says.“It af- this asahugeproblem inour in thisresearch, becauseIsee ders. the symptomsofeatingdisor- effective treatments toalleviate Tong, PhD, focusesonfinding associate professor Qingchun option. Thatiswhythelabof eating maynotalwaysbean ing disorders, however, healthy individual’s day-to-daygoal. ofevery healthy shouldbeapart a constantreminder thateating foods andthenext-bestdietare healthy lifestyle. Trendy super- co-regulated byneuronsthat alsoregulateemotional states. inobesityand anorexia are feedingbehaviors Our ideais thatdefective “We’re tounderstand trying Dr. Tong’s research spans “I’ve alwaysbeeninterested For thosesufferingwitheat- component to living a component tolivinga ing aproper dietisakey here isnosecret thateat- Unlocking themysteries of eating disorders can changeactivityinoppo- disorders. Since theneurons inregulating important eating meaning thatpathwaycould be controls emotionalchanges, brain aggression center, which brain feedingcentertothe a neuralpathwayfrom the and histeamhave discovered ment offeedingabnormalities. which cancausethedevelop- activity intheaggression center, able tomanipulatetheneural tional changes.Thelabisalso whether theyexperienceemo- nipulate neuralactivitiestosee and hislabare abletoma- typical feedingcenter, Dr. Tong cure bothobesityandanorexia.” thatcanpreventsuitable drug or biology, andseconddesigna neurons to first,understandthe that we can identifythebrain Dr. Tong explains.“We hope for future cures orprevention,” we candiscover effective targets underlying development sothat can reveal keymechanisms tive treatments forthedisease. higher duetonoknown effec- much smaller, thefatalityrateis rate forpatientswithanorexia is other side,thoughtheincidence are affected by obesity. On the 30 percent ofAmericanswho treatment forthemore than medication astheonlyeffective biology ofeatingdisorders, with have sufficientknowledge ofthe also regulate emotionalstates.” In hisresearch, Dr. Tong Using animalmodelsina “The hopeisthatourstudy Scientists currently donot Medical School in2009. He joinedthestaffat McGovern state Medical Centerin2003. his PhD from SUNYDown- grams inChinabefore earning undergraduate andmasterspro- anorexia.” symptoms ofbothobesityand key neurons, you canreduce the inthose behavioral intervention of exercise. So ifyou canuse programs incertain participate says. “You cangothegymand ments already exist,” Dr. Tong instead ofthrough medication. through behavioral treatments ties tocontrol eatingdisorders of trainingthoseneuralactivi- his research istofindameans behavior. One ofthegoals ties thatdirect regulated feeding to studybrainneuronal activi- able neuraltracingtechnologies, availoptogenetics andnewly - advanced technologies, suchas It wasthelogicalnextstep.” ral program thatcontrols both. because I think it’s the same neu- interested inanorexia research, can gobothways,Ibecame when Idiscovered thatneurons in obesity,” Dr. Tong says.“But controlled by thesame pathway. and emotionalregulation canbe Tong hasconfirmedthatfeeding of thebiologicalprocesses, Dr. refusal toeat.By regulating each control overconsumption or site ways,theycanbeusedto Dr. Tong completedhis “Some behavioraltreat- Dr. Tong’s labisusing “My research wasoriginally ” — Dr. Qingchun Tong IMMPACT REPORT 77 • • • •• • • • Dr. Qingchun Tong is on a mission to find treatments for both sides of the eating disorder spectrum. for both sides of the eating disorder is on a mission to find treatments Tong Qingchun Dr.

— Dr. Qingchun Tong Qingchun — Dr. Dr. toviewthebody’s Melissa Aldrich technology usesspecialized lymphatics. • 8 IMMPACT REPORT IMMPACT REPORT 9 • • • • Profiles in research in Profiles Dr. Aldrich says her research research Aldrich says her Dr. first goal is catching “Our Aldrich earned her PhD Dr. of heard even “I hadn’t the to spread order In committee developed “Our is Aldrich, her work Dr. For pill for lymphedema is “A approach. has a two-pronged and the lymphedema early, thethe second is finding says. Aldrich Dr. cause,” than is more “Lymphedema just a disease of disruptionof duethe lymphatic channels to surgery and radiation – if it that, then everyone who were an had surgery would get it. It’s and autoimmune-like disorder, cellular and molecular are there to be yet factors that have that could be targets uncovered lymphedema with a for treating pill, or other therapeutics.” the MD in immunology from Graduate Anderson UTHealth School and joined the IMM faculty in 2007. joining lymphedema before lab – and this was Sevick’s Dr. in cancer of working after years added. Aldrich Dr. research,” about lymphedema, word served Aldrich recently as Dr. chair of a committee with the organization LE&RN, advocacy & Education Lymphatic Network. Research for centers of standards for the diagnosis excellence of lymphatic and treatment diseases. This will help patients understand their options and Dr. make informed decisions,” Aldrich said. all about the patients. my main goal, at the top of my bucket list. A pill, or an easy treatment.” The study started in 2016, research The key to the visualizing until now, “Up “With the tool, starting in the study also Patients you can halt it and even turn it turn can halt it and even you around.” cancer breast 60 and so far, University The patients from Cancer MD Anderson Texas of been enrolled. Center have 75-100The goal is to include Shaitelman, patients. Simona of MD, associate professor radiation oncology at MD Anderson, is the co-principal on the grant. investigator imaging is the innovative which was invented technology, professor PhD, Sevick, Eva by of the Center for and director and Nancy Imaging Molecular and Rich Kinder Distinguished Disease Chair in Cardiovascular Rasmussen, and John Research, in the assistant professor PhD, Imaging. Center for Molecular what was going on inside the lymphatic system was like and looking at a black box guessing. I am fortunate to with engineers who have work the best system in developed the world that can see if the Dr. working,” lymphatics are Aldrich says. we cancer treatment, before skin to patients’ look through developing see whether they are times we lymphedema. Many the standard before catch it well which is just old-fashioned way, is waiting until limb volume normal.” above 5-10 percent their blood tested for have immune abnormalities before cancer surgery and at 6, 12, and radiation 18 months following treatment. Shining a light a Shining on a neglected system a neglected on

e all are familiar with e all are skeletal the body’s system, muscle

A clear fluid comprised of 10 million people About Aldrich, who investigates Dr. the exact one knows “No

system, and blood system.system, and blood what about the lymphatic But a neglected system? Considered intosystem, it only came a decadescientific focus about realized ago when researchers and of vessels that this network immune organs filters 2 to 3 our gallons of lymph through bodies each day. immune cells, large proteins, and cell waste fluid, lymph can pose a serious problem for cancer patients presenting fluid as lymphedema – excess pooling in limbs and in areas been lymph nodes have where removed. with lymphatic disease in live and Melissa States, the United an assistant Aldrich, PhD, in the Center for professor predicts Imaging, Molecular as that number will increase cancer survivorship rates grow. immune factors that influence lymphatic dysfunction and translates lymphatic imaging technology to the clinical setting, is leading a five-year of Health- Institutes National cancer funded study of breast at high risk of patients who are lymphedema. developing cause of lymphedema – surgery, blamed radiation, and cancer are – and it can be permanent,” Aldrich explains. “What Dr. trying are we to do is to detect lymphedema at the developing early stages – the earlier you it, the earlier catch it and treat W Dr. Ali Azhdarinia’s research couldleadtosaferandmore effective cancer treatmentsdrug delivery. intumor-specific 10 • IMMPACT REPORT IMMPACT REPORT • • • • 11 Profiles in research in Profiles “Collectively, our drug “Collectively, in interest Azhdarinia’s Dr. tailored are treatments “Now and specifically seeks out tumorand specifically seeks more surgeons to cells to allow cancerous remove efficiently healthycells without cutting tissue. help surgicaldesign strategy can and nonsurgical populations,” Azhdarinia explains. “We Dr. the same concept for both, have instead of just putting but now us to allow to dye a fluorescent can substitute see the tumor; we compounds to kill the toxic tumor.” while at The his field developed Graduate Texas of University Sciences, School of Biomedical in he obtained his PhD where of pharmacology and the area recalls nuclear medicine. He that at the beginning of his cancer treatment career, research was not nearly as individualized as it is today. to the biology of the cancer and going in so many different are Azhdarinia says. Dr. ways,” strategy was: why not our “So, can take imaging, since you it, and see uptake and measure apply it to targeted therapies much can monitor how so we the tumor and see how reaches you Potentially, it responds? the ultimate goal of can achieve much drug needs toseeing how to get get to that tumor in order want.” you the response “We are developing new developing are “We have concepts that Using of three a toolkit have you “If lab has been Azhdarinia’s chemotherapy. strategies to take imaging use we compounds, and then an them not only to deliver on, going isotope to see what’s a cytotoxic but also to deliver Dr. the cell,” agent that will kill Azhdarinia says. been clinically adopted in nuclear medicine for nearly the Azhdarinia half a century, lab has attached chemotherapy with radioactive treatments compounds to see exactly where the drug is going and how the it is at destroying effective tumor. or four drugs that may help the out want to figure patient, you which one is the best for each Azhdarinia Dr. individual,” on working are says. “We us to methods that will allow each drug see how noninvasively interacts with the tumor so we which will be most can predict effective.” on tumor-specific working drug delivery since 2010 and in 2014 made a breakthrough an NIH grant after receiving for a that supported research compound that uses fluorescent the same chemistry platform that is used for delivering This project chemotherapy. consists of a peptide that is dye attached to a fluorescent of cancer treatment of cancer — Dr. Ali Azhdarinia — Dr. A vision for the future the for A vision ”

erhaps one of the scariest the throughout words Whether world is cancer.

Research all over the world over all Research my lab focuses “Specifically, cancer treatments current In can problems Similar We are working on methods that will allow us to noninvasively see how We will be most so we can predict which drug interacts with the tumor each effective. it is a family member or friendit is a family member orwho has been diagnosed, at work program an awareness cancer are or school, chances life in will affect a person’s fact, In one way or another. the American Cancer Society estimates that nearly one in every Americans will three cancer in their lifetime. develop into finding has been poured in However, for cancer. a cure the lab of associate professor Ali Azhdarinia, the goal PhD, is to apply new technologies to that already enhance treatments exist. on using imaging techniques to see and treat we how improve Azhdarinia says. Dr. disease,” spread for tumors that have toxic extremely the body, across chemotherapy is injected into which goes to the the body, With tumor and wipes it out. you however, this approach the drug where cannot control goes, so while wiping out a also are you tumor, dangerous normal tissue. affecting healthy, arise due to chemotherapies not being potent enough to completely kill off a cell, or if a tumor adapts and to a certainbecomes resistant P “ 12 •

IMMPACT REPORT Profiles in research “ A Alzheimer’s, Parkinson’s, andHuntington’s. That wouldbeourgoal –tohalttheprogressionofbonemarrow cancer, and herlabhave discovered a out ofbalance,Dr. McCarty Chair inStem CellBiology. Bob Graham Distinguished Dr. McCarty, theAnnie and out ofbalance,itdies,” explains homeostasis. If thecellbecomes proteins in thecorrect balance, balanced tounbalanced. cells makethatfatalswitchfrom the IMM,isdiscovering how and Regenerative Medicine at associate professor ofStem Cell level, Nami McCarty, PhD, level, could bestoppedthere? atthecellular which allstart believed to have Parkinson’s. and 1millionAmericansare the ageof65hasAlzheimer’s; cancer; 1in10Americansover of uswillbediagnosedwith troubling disease. About 38% signaling canceroranother or grow, thatcanspelltrouble, balance. When cellsdie,fold, to keepingourentire bodyin in ourcells? sense ofbalanceisactuallybased us. But didyou know thatthis These are goalsformanyof Detecting how cellsbecome “Healthy cellshave tomake Working attheintracellular But whatifthesediseases, Cellular homeostasisiskey balanced checkbook. balanced checkbook. balanced diet.A balanced life.A Translating research PhD in medicine chemistry PhD inmedicinechemistry and Huntington’s.” cancer, Alzheimer’s, Parkinson’s, progression ofbonemarrow would beourgoal–tohaltthe diseases,” shesays.“That therapies tothesedevastating targets,whichwill providedrug autoimmune diseases. neurological diseasesbutalsoto her research appliesnotonlyto in cancer, Dr. McCarty says neurological research.” Alzheimer’s andexpandtothe “I wouldliketonow addin in thecancerspace,” shesays. a lotandbeenwell-funded and Ihave beenabletopublish development, model fordrug multiple myeloma. inactivity inbloodcancer, a protein that regulated overloaded anddies.” get ridofthetrash;cellgets she explains.“Thecellscan’t trash mechanismforthecell,” Parkinson’s. is afactorinAlzheimer’s and Dr. McCarty saysshebelieves, for thecell.Thissameprotein, cancer progression, actingasfuel protein thatisimplicatedin in thelab Dr. McCarty earnedher “Ultimately, we willcreate Having made thesefindings “Multiple myeloma isagood Dr. McCarty’s labdiscovered “This protein islikethe ” — Dr. Nami McCarty research.” is tomakesomethingofmy Iampassionateabout “What looking forabigchange. the neurosciences, sheagainis broaden herstudiestoinclude cancer. Andwithherintentto focus from immunologyto McCarty switchedherresearch position.” meformy time, interviewed who wasthedirector atthat Irma Gigli andDr. Tom Caskey, myself backthen,” shesays.“Dr. S. Sarofim Research Building. the 229,000-square-foot Fayez one ofthefirstfacultytooccupy Molecular Medicine andwas was recruited totheInstitute of discovered. based onagenesignature she Infectious Diseases in2006, Institute ofAllergyand Award, K22,from theNational Research ScholarDevelopment central tolerance.She received a of immunehomeostasisand investigating mechanisms School, whichinvolved Institute andHarvard Medicine at theDana-Farber Cancer pursued postdoctoralresearch Purdue University in2000,and and molecularpharmacologyat “I candothis,” shesays. Upon joiningtheIMM,Dr. “I hadthewholefloorto That wasthesame year she IMMPACT REPORT • • • •• • • • 1313 Dr. Nami McCarty is applying her research in cancer to neurogical and autoimmune diseases. in cancer to neurogical McCarty is applying her research Nami Dr.

Frances Escriva, Carl F. Jaedicke, andC.Ronald Dorchester. Members oftheBovay Foundation includeEdward R.Naumes, from left,Michael L.Patrick, Larkin Peggy Kelly, 14 • IMMPACT REPORT IMMPACT REPORT • • • • 15 Donor spotlight Donor Funded by the Bovay the Bovay by Funded “When telomeres age, we evidence has now team His a lot to learn and have “We 2019, keeping December In largely dependent are “We the team also is Foundation, of healthylooking at the science aging. tips of the (the protective shortenchromosome) and, as a stem cells can no longer result, cells in fatdivide to renew says. Kolonin Dr. tissue,” stem cell that in obesity, depletion is accelerated, which diabetes underlies premature is now The group development. feeding affects looking at how stem cell exhaustion in fat, as as in other tissues, and how well can be applied this knowledge in preserving skeletal muscle fitness. many hypotheses to test, but aligned within our the stars are team to make important new that will improve discoveries says. Kolonin Dr. health,” mantra “build with the Bovay Kolonin Dr. gave,” on what you the recipients and his team were the Bovay of another gift from to support their Foundation work. important and innovative Foundation’s upon the Bovay Kolonin Dr. generosity,” NIH support, have says. “We of NIH want but reviewers preliminary data, they want the nitty gritty details to get started, and that is why this support is so vital.” Mikhail Kolonin, PhD, PhD, Kolonin, Mikhail and his team Kolonin Dr. published to “According is investigating group His helped to create the IMM’s the IMM’s helped to create Center for Metabolic Research Diseases. Center of the IMM’s director and Degenerative for Metabolic is the holder of Diseases, Jr. the Harry E. Bovay, Chair University Distinguished and Research in Metabolic on the principal investigator an endowed Lectureship, Bovay joined the series. He lecture IMM faculty in 2007, earning State Wayne from his PhD and completing University at a postdoctoral fellowship MDTexas of University The Anderson Cancer Center. focused their research have fat plays in cancer on the role The and aging. progression that fat has shown work group’s of the progression cells promote cancers and and breast prostate to resistant makes them more chemotherapy. of statistics, 15 to 25 percent deaths could have cancer-related preventing by been avoided that with is possible It obesity. or other surgery, weight-loss can we measures, prevention cancer progression, also reduce the risk of cancer recurrence, use it as a cancer or even says. Kolonin Dr. treatment,” experimental therapies targeting fat tissue as a potential complementary to approach cancer treatment. Building Bridges Building

The Bovay Foundation – Foundation Bovay The

s a child, Harry E. a enjoyed Jr. Bovay poem that hung in

That concept of building in the lived Bovay he formed the 1991, In was one of the Bovay

his father’s office. Called “The his father’s Allen Will by Builder” Bridge it describes an old Dromgoole, who builds a bridge traveler a wide chasm after across safely – not for himself crossing who may but for the youth after him. travel as Bovay’s for others remains Jr. legacy in the Harry E. Bovay Foundation. for most of area Houston graduation his life following in Cornell University from He 1936 as a civil engineer. Engineers established Bovay his retirement and, following in 1984, established the Mid- Telecommunications South until a there working Company, his death infew months before 2011 at the age of 96. Foundation Jr. Harry E. Bovay to support education and in community development Scouts, the Boy rural areas, and other charities, including efforts at the IMM. research original donors to the IMM’s Frontier $200 million New Campaign, which established the IMM as the research gift of His institute it is today. the Harry$1.5 million created Distinguished Jr. E. Bovay Chair in Metabolic University and his generosity Diseases, A 16 • IMMPACT REPORT T (ACM). Pathogenic andcausalvariants are (DCM), andarrhythmogenic cardiomyopathy cardiomyopathy (HCM),dilatedcardiomyopathy with cardiomyopathies, includinghypertrophic several hundred casesandtheirfamilymembers cardiomyopathies: We of have arepository for large-scalemulti-centerefficacyclinicaltrials. clinical trials.Thefindings provide theplatform randomized placebo-control double-blindstudies are extendedtohumanpatientsthrough pilot Thefindingsinthemodelsystems interventions. and therapeuticgeneticpharmacological dysregulated pathogenicpathwaysforpreventive integrated approach isusedtoidentifythekey and DNAmethylationincardiomyopathies. The dysregulated pathways,chromatin remodeling, expressed codingandnon-codingtranscripts with thegenomicstudiestoidentifydifferentially sequencing. Genetic discoveries are thencoupled by wholeexomeanalysis isperformed andgenome sudden cardiac failure. deathandheart Genetic cardiomyopathies, whichare causesof important diseases. Thefocusisprimarilyonhereditary the causalgenesforhumancardiovascular molecular geneticstudiesaimedatidentifying research withhuman programs atthecenterstart Professor. Lombardi, MD,PhD, Adjunct Assistant Professor; AJMarian, MD,Professor; Raffaella targeting ofthepathogenicgenesandpathways. diseases inhumansthrough identification and clinicaltrials. industry-sponsored research activities,includingNIH-and clinic, whichisutilized forclinical Clinic. Thecenteralsohasa research disorders attheCardiovascular Genetic to patientswithgeneticcardiovascular provides specialized clinicalservices diseases inhumans.Thecenter to prevent andtreat cardiovascular objective ofutilizingthediscoveries cardiovascular diseaseswiththe genomics, andpathogenesisof on elucidationofmoleculargenetics, CENTER FORCARDIOVASCULARGENETICS I. Human molecular genetic studiesof The research programs are asfollows: Research Programs: General theme oftheresearch programs: The Faculty: Priyatansh Gurha, PhD, Assistant Mission: To prevent andtreat cardiovascular established in2006,focuses Cardiovascular Genetics, he IMMCenterfor Chair inCardiovascular Research JamesT. Distinguished Willerson Center Director &Professor AJ Marian, MD cardiomyopathies. sponsored clinicaltrialsin inindustry participates HCM wasrecently completed. Thecenteralso pilot study(HALT-HCM) inpatientswith An NIH-sponsored double-blind randomized cardiomyopathy.clinical trialsinhereditary multi-center trials aswell asindustry-sponsored investigator–initiated singlecenterpilotclinical are current underway. outcomes are analyzed. Several active programs cardiaceffects onsurvival, function,andclinical inmodelorganismsandtheir interventions are targetedthrough geneticandpharmacological pathways identifiedthrough integratedgenomics pathways incardiomyopathies: Dysregulated targeting. findings are usedforpreventive andtherapeutic specific histonesandproteins. Theintegrated and chromatin remodeling by ChIP-Seq of RNA-Seq, DNAmethylationanalysisby RRBS, and includewholetranscriptomeanalysisby studies predominantly relate toDCMandACM and mousemodelsofcardiomyopathies: The and familymembers. We are actively recruiting additionalprobands have failure. advanced thegeneticcausesofheart disease-causing genesand identification ofnew probands and familymembers.Thesestudieshave identified by wholeexome sequencinginthe IV. ClinicalStudies: in Thecenterparticipates III. Therapeutictargetingofdysregulated failureII. Genomics studiesofhumanheart IMMPACT REPORT • • • • 17 Methylation in Human Dilated Cardiomyopathy. Cardiomyopathy. Methylation in Human Dilated S.J.; S.; Matkovich, Marreddy-Cheedipudi, M.; M.J.; Sweet, X.; Robertson, C.; Hu, Coarfa, Willerson, J.; L.; Cleveland, M.; Mestroni, Taylor, Res. Circ 2019 Apr AJ. Marian, P.; Gurha, J.T.; PMID: 30739589 12;124(8):1198-1213, Acti- DNA Damage Response/TP53 Pathway is vated and Contributes to the Pathogenesis of A/C Dilated Cardiomyopathy Caused by Lamin R.; Karmouch, S.N.; Lombardi, Chen, Mutations. M.R.G.; Taylor, G.; Czernuszewicz, J-Y.; Tsai, J.; AJ. Marian, P.; C.; Gurha, L.; Coarfa, Mestroni, PMID: Res. 2019 Mar 15;124(6):856-873. Circ 30696354 Hypertrophy Regression with N-AcetyLcysTeine A in Hypertrophic CardioMyopathy (HALT-HCM): Randomized Placebo Controlled Double Blind J.; L.; Chang, Li, Y.; Tan, AJ.; Marian, Pilot Study, J.T;. Willerson, M;. M.; Rahbar, Hessabi, P.; Syrris, D;. N.; Bluemke, C.; Kleiman, B.; Liu, Cheong, Res. 2018; 122: 1109-1118 Circ S. Nagueh, PMID: 29540445 LAB MEMBERS PhD.; Auguste, Post-doctoral fellows: Gaelle PhD Sirisha C Marreddy; Leila Rouhigharabaei, Siyang Fan Yuan, Research assistant: Ping MS Research associate: Grace Czernuszewicz, RN Tan, Yanli Research and clinical nurse: Inducible polymorphic ventricular tachycardia in a mouse model of arrhythmogenic cardio- myopathy. sponsored clinical trials to test efficacy of an modulator on improve symptoms and ATPase exercise tolerance in patients with obstructive (Maverick) and non-obstructive (Explorer) hypertrophic cardiomyopathy. N-Acetylcysteine in Hypertrophic Cardio- myopathy) clinical trial (ClinicalTrial.Org NCT01537926). molecular pathways that link the genetic mu- tations to the clinical phenotype in patients - including delinea with cardiomyopathies, tion of the mechanical signaling pathways regulated at the intercalated discs. etic and transcriptomic changes, including including etic and transcriptomic changes, non-coding RNAs and histone modifications in hereditary cardiomyopathies. and sudden cardiac death. KEY PUBLICATIONS Exercise Restores Dysregulated Gene Expression Arrhythmogenic Cardiomy- in a Mouse Model of Yuan, S.; J.; Fan, S.M.; Hu, Cheedipudi, opathy. G.; Robertson, J.; Czernuszewicz, Karmouch, P.; H.C.; Moore, Y.; Yao, C.; Hon,g K.; M.J.; Coarfa, Cardiovasc AJ. Marian P.; X.; Gurha, Wehrens, PMID: 31350552 Res. 2019 Jul 26. Genomic Reorganization of Lamin-Associated Associated Domains in Cardiac Myocytes is with Differential Gene Expression and DNA •Maverick & Explorer studies: Industry – HALT-HCM (Hypertrophic Regression with •HALT-HCM •Identification and characterization of the •Identification and characterization of epigen- Molecular genetics, genomics, pathogenesis, and treatment of and treatment pathogenesis, genomics, Molecular genetics, hereditary cardiomyopathies genomic remodel- link the causal mutations to re- The ing and to the pathogenic pathways. are identified sponsible molecular mechanisms studies in ge- through molecular mechanistic models and cultured netically modified animal then The mechanistic discoveries are cells. utiliz- utilized to intervene in model organisms, ing genetic and pharmacological approaches order in that target the pathogenic pathways, to prevent evolving the phenotype and reverse These or attenuate the established phenotype. findings in the model organisms are extended to human studies through pilot randomized placebo-controlled double-blind clinical trials. are pursued through if favorable, The findings, collaborative large-scale clinical trials. RESEARCH PROJECTS •Identification of causal genes for heart failure AJ Marian, MD AJ Marian, Cardiovascular Genetics Director of the Center for Professor and WillersonResearch Chair in Cardiovascular Distinguished T. James Our long-standing research objectives have ACM Arrhythmogenic Cardiomyopathy (ACM): Hypertrophic is Cardiomyopathy (HCM): HCM Dilated Cardiomyopathy (DCM): DCM is The overall approach entails an integrated been to delineate the molecular genetics, and pathogenesis of hereditary genomics, cardiomyopathies in humans and apply the discoveries to prevent the evolving and reverse the established phenotypes of heart failure and have active research We sudden cardiac death. programs in three common forms of hereditary cardiomyopathies: is an enigmatic form of hereditary cardiomy- opathies that clinically presents with cardiac and sudden cardiac heart failure, arrhythmias, A unique particularly the young. in death, feature of this disease is a gradual replacement There of cardiac myocytes with fibro-adipocytes. ACM. is no effective therapy for the most common form of hereditary cardiomy- affecting ~ 1 in every 500 individuals opathies, The affected individu- in the general population. als are typically asymptomatic and sudden cardiac death is often the first manifestation of HCM is the most common cause of this disease. While there sudden cardiac death in the young. are effective therapies to alleviate patient’s there is no effective therapy to symptoms, prevent or reverse process. the disease genetically the most heterogeneous form of hereditary cardiomyopathies and a major cause of heart failure and heart transplantation in the The affected individuals often present young. cardiac arrhyth- with symptoms of heart failure, sudden cardiac death. and sometimes, mias, There are a number of effective pharmacologi- cal and non-pharmacological therapies for DCM but currently there is no cure for DCM. approach that includes human molecular genet- ic studies through high throughput whole exome and genome sequencing to identify the causal followed by genomic stud- genes and mutations, including transcriptomics and epigenetics ies, to define molecular remodeling of chromatin in The aim is to the presence of causal mutations. CARDIOVASCULAR GENETICS FOR CARDIOVASCULAR CENTER 18 • IMMPACT REPORT CENTER FORCARDIOVASCULARGENETICS contribution towardshumanHF. andtheir these regulatorsincardiacphysiology tissue andcelltype-specificcontributionof mousemodelstoinvestigate the and several using inducedpluripotentstemcells(iPSCs) isunknown.enriched lincRNAsinheart We are manifestation ofHF. The roleofKDM5andCM non-coding RNAs(lincRNA)inthephenotypic novel cardiacmyocyteenrichedlongintergenic identified anepigeneticregulatorKDM5, anda Lamin Associated DomaininHumanHFand we uncoveredtheroleofDNAmethylationand failure(HF).in humanDCM/heart Recently, transcription andensuingcardiacphenotype reprogramming ofepigeneticcodegovernsgene ACM. We havenowbeguntoinvestigatehow of miR-184anditsroleinthepathogenesis studies haveidentifiedepigeneticdysregulation to cardiacdysfunctionandfailure. Myprevious leads these interlinkedprocesseseventually maturation ofmyocytesandhowalteration RNAs inproliferation, differentiation, and the functionofepigeneticsandnon-coding failure. thistheme,Within wearestudying contribute tothepathogenesisofheart coordinately regulategeneexpressionand understand themolecularmechanismsthat The mainobjectiveofmyresearchisto Assistant Professor Priyatansh Gurha, PhD human heart failure(HF). human heart Heat plotofdifferentiallyexpressedtranscript anddysregulatedupstreamtranscriptionalregulators in authors). Feb 11. PMID:30739589(#Co-corresponding man DilatedCardiomyopathy. Circ Res. 2019 Gene ExpressionandDNAMethylationinHu- Cardiac Myocytesis Associated withDifferential Reorganization ofLamin-AssociatedDomainsin Willerson, J.T.; Gurha, P#;Marian, AJ#. Genomic M.E.; Taylor, M.;Mestroni, L.;Cleveland, J.C.; Coarfa, C.;Hu, X.;Robertson, M.J.;Sweet, Marreddy Cheedipudi, S.;Matkovich, S.J.; 34(3):241-245. diseases. CurrOpinCardiol.2019May; Gurha, P. NoncodingRNAsincardiovascular KEY PUBLICATIONS •Identification andcharacterizationofmo- •Role oflncRNAsinthepathogenesiscardio- RESEARCH PROJECTS failure epigenetic regulationinheart Molecular mechanismsandfunctionsofNon-codingRNAs heart failure. heart demethylase KDM5incardiomyopathiesand lecular mechanismsandfunctionsoflysine failure. myopathies andheart Research assistant:JordiCostePradas LAB MEMBERS ing authors). 2016 Sep2;119(6):731-50(#Co-correspond- In Vitro. *AuthorscontributedequallyCirc Res. Pathway andLeadstoEnhanced Adipogenesis Hypermethylation andSuppressionoftheE2F1 2 DownregulatesmiR-184 Through CpG J.T.; Marian, AJ#. KnockdownofPlakophilin Gurha, P.*#; Chen, X.*;Lombardi, R.; Willerson, IMMPACT REPORT • • • • 19 All of us have had, or will have, one of our had, or will have, All of us have under the direction of Dr. Myriam Fornage, Fornage, Myriam of Dr. under the direction making global leaders in their field, and are are susceptibility in the study of notable progress in cognitive decline and age-related to stroke cardiac function. A significant fraction of sudden rhythm disruptions from that arise death results processing in the proteins in genetic variation the electrical activity within the heart. Our is an Ashish Kapoor, Dr. newest faculty member, that shown We have emerging leader in this field. kidney injuryblood associated with increased the emergence of auto- from results pressure unexpected antibodies that damage tissues. This role of lab points to a Doris’ Dr. finding from in creating immune system genetic variation continues to advance Teng Ba-bie disease risk. Dr. understanding of susceptibility to atherosclerosis new drugand the interplay between targets, such cells. As our uptake by as PSCK9, and lipoprotein understanding of the complexity of information in the genome expands, storage and retrieval is addressing Wang Sidney our colleague Dr. to assess, extract, and exploit new approaches of genomic complexity that will inform levels in this field. work in life disrupted common by close relationships for Human the Center disease. In cardiovascular the opportunity have to work we Genetics, for change, pushing forward the knowledge medicine draws toward which current from new insights and new opportunities for disease prevention. PhD A. Doris, Peter & Professor Director Center Distinguished Holdsworth Mary Elizabeth and Inflammatory Metabolic Chair in University Disease Research

he Center for Human Genetics Genetics for Human he Center new to generate works about genetic understanding

An emerging concept developing in our An emerging concept developing in the laboratories of our investigators Progress HUMAN GENETICS FOR HUMAN CENTER

risk for common cardiovascular cardiovascular risk for common that information diseases and to use therapies for to identify effective blood pressure these diseases. High that drives is an amplifying element disease risk from cardiovascular heart,stroke, and kidney disease. in middle and These diseases emerge interlinked with later life and so are of aging. The the normal processes makes us unique that genetic variation individuals and that has been passed our risk of these impacts our parents to us from targets the identification of work diseases. Our diseases genes that contribute to cardiovascular in these which variation and the mechanisms by the biological pathways in which genes re-shape disease emerges. laboratories is that an important element of is system disease of the cardiovascular chronic a persistent state of that these diseases involve For example, in atherosclerosis, inflammation. immune cells by wall is invaded the blood vessel plaques and the danger posed in atherosclerotic inflammation in of the ongoing level may reflect need a better understanding of these We them. in which our inflammation” of “sterile processes to in response immune systems become activated need We the emergence of damage to our tissues. that understanding of the genetic variants greater determine whether these inflammatoryresponses The advance. or even active subside or remain challenge of identifying these genetic variants is the fact that there complex by is made more affecting our immune a lot of genetic variation to be able to adapt to the order In responses. continuous and rapid mutation of pathogens like viruses and bacteria, our immune systems harbor can variation Such genetic variation. extensive to new us a head-start or in responding provide risk it also can create pathogens. But evolving of disease later in life. As our living standards lengthened, the have and our lives increased have earlier in life can turn into provided advantages our risk of increasing to our health by threats disease. cardiovascular chronic and important insights. continues to yield exciting human population geneticists, working Our T 20 • IMMPACT REPORT blood pressurebuthave norenalinjury. generate antibodies. of havehigh levels They the immunoglobulingene. These animalscannot renal injuryinourmodelorganism, wedeleted renaldisease. hypertensive disease driver. antibody-producing Bcellsmaybethemain adaptive immunesystemandsuggeststhat confirms ourattributionofdiseasetothe immune responsesinthismodel. This work function limitrenaldiseaseinhypertension. autoimmune disease. cell functionandleadstoantibody-mediated The mutationinStim1blocksnormal T andB cytes comprisetheadaptiveimmunesystem. gene inlymphocytefunction. T andBlympho - genetic deletioninthegene, Stim1. This isakey encodes antibodies. We alsohaveidentified in theimmunoglobulinheavychaingene, which renaldisease. the emergenceofhypertensive test theminthemodel. disease and treatment approachestoprevent can takewhatwehavelearnedandconceiveof disease.genetic differencescandrivekidney We this modelprovidesameanstoinvestigatewhat gressive renalinjury, otherlinesdon’t. Therefore, is alsopresentintheserats. Somelinesgetpro- renaldiseaseriskseeninhumans hypertensive that havehighbloodpressure. The dichotomy of genetic modelcomprisinginbredlaboratoryrats To trytofillthisknowledgegap, westudya diseaseinsomepeoplebut notothers.kidney knowledge ofhowhighbloodpressurecreates predisposition. At presentwehave almostno predicted byfamilyhistory, indicatingagenetic in patientswithhighbloodpressureisbest of renalinjury, buttheriskofrenaldisease CENTER FORHUMANGENETICS Loss of antibodies reveals abacterialinputto Loss ofantibodiesreveals To provethatantibodiescauseshypertensive Genetic deletionofantibodieseliminates adaptive We haveusedadrugtoprevent Pharmacological suppressionof T andBcell We geneticvariation haveidentifiedimportant Genes influencingantibodyformationaffect What wehavelearnedsofar: High bloodpressureisafrequentcause Disease Research DistinguishedUniversityChairinMetabolicandInflammatory Mary ElizabethHoldsworth Professor/Center Director Peter A. Doris, PhD Genetics ofcardiovascularendorganinjury contribute todiseaserisk. alter thecontrolofantibodyformationandmay Common geneticvariantsoccurinhumansthat rats giveinsightintorenaldiseaseinhumans? rent interest: reduced. rats pronetoinjury, renalinjurywasmarkedly ney. When antibioticsaregiventohypertensive antibodies toformthatareharmfulthekid- to thisbacterialantigenicinputandmaycause genetic differencesinimmunefunctionrespond pathogenic bacteriathatliveinthegut. The indicates thattheinfectingbacteriaarenon- free frombacterialpathogens. Bloodculture liveinanenvironment thoughthey even ment, experiencebloodinfection(sepsis), they antibodies areraisedwithoutantibodyreplace- immunesystem. the hypertensive antibodies provide(rightpanel). This knowledgemayallowustoblocktheir harmfuleffectswhilestillallowingnormalprotectionsthat createdisease.We wanttoknowthetargetsoftheseantibodiessothatwecanunderstandhow they formed. This indicatesthattherearepathogenicantibodiescreating disease(centerpanel). We canblockitwithantibiotics, orwecanblockitbydeletingthegene from whichantibodiesare to activateanimmuneresponseandthatwecanblockthis reducedisease. genes contributingtoantibodyformation(Leftpanel). We alsodiscoveredthatgutbacteriaareable renaldiseasegenetics includethedetectionofgeneticvariationin Our discoveriesinhypertensive Do thepathogenicmechanismsactivein questionsthatarethefocusof ourcur- Key ratsunabletoproduce When hypertensive Joshi, BS Research assistants: Yaming Zhu, MD; Aniket Post-doctoral fellow:IshaS. Dhande, PhD LAB MEMBERS Genes andImmunity. 2019. InPress rat.stroke inthespontaneouslyhypertensive Doris. NaturalgeneticvariationinStim1creates M.J. Hicks;S.E. M.C.Wenderfer; Braun;P.A. Dhande, I.S.;S.C. Kneedler; Y. Zhu; A.S. Joshi; sion. J. Amer. Association.Heart 2019. InPress - signaling andcreatesrenalinjuryinhyperten Doris. Stim1polymorphismdisruptsimmune M.J. Hicks;S.E. M.C.Wenderfer; Braun;P.A. Dhande, I.S.; Y. Zhu;S.C. Kneedler; A.S. Joshi; 31608789. rat. PhysiologicalGenomics,2019PMID: susceptibility inthespontaneouslyhypertensive immunoglobulin heavychaincreatesstroke A. Doris. Germ-linegeneticvariationinthe M.J. Hicks;S.E. M.C.Wenderfer; Braun;P. Dhande, I.S.;S.C. Kneedler; A.S. Joshi; Y. Zhu; KEY PUBLICATIONS IMMPACT REPORT • • • • 21 KEY PUBLICATIONS D.P.; H.H.H.; Hibar, Adams, C.L.; Satizabal, R.; J.M.; Schmidt, Wardlaw, M.; Fornage, A.; Debette, Villringer, P.L.; C.; De Jager, DeCarli, S.E.; Shulman, Medland, V.; S.; Gudnason, S.; Ikram, Seshadri, P.M.; Thompson, J.M.; Genetic architecture of subcortical brain M.A. Nat Genet. structures in 38,851 individuals. 2019 (in press) X.; Gottesman, B.; Jian, Yu, S.; Tiedt, D.; Sun, M.; E.; Dichgans, Boerwinkle, T.H.; Mosley, R.F.; A prospective study of serum me- M. Fornage, Neurology. tabolites and risk of ischemic stroke. 2019; 92:e1890-e1898. S.; K.H.; Zahid, Wade, M.; Chaffin, A.V.; Khera, M.; Senol-Cosar, R.; Distefano, J.; Xia, Brancale, K.G.; Lander, Aragam, A.; M.E.; Bick, Haas, O.; H.; Fornage, Mason-Suares, G.D.; E.S.; Smith, L.M.; N.J.; Kaplan, Timpson, M.; M.; Lebo, Weight Polygenic Prediction of S. Kathiresan, Adulthood. Birth from to Trajectories and Obesity Cell. 2019; 177:587-596. LAB MEMBERS PhD program; Yang, Yunju Graduate students: MPH program Nitesh Enduru, Research assistants: Lassana Samarakoon, Biostat- MS, Thomas, Biostatistician; Emy MPH, PhD Wang, istician; Ping Biostatistician PhD, Research associate; Rui Xia, nitive function in diverse Hispanics/Latinos. blood pressure using gene-lifestyle interac- In particular, tions and pathway analysis. discovering how depression and anxiety affects genetic risk of hypertension. tion) variants that influence risk for brain small vessel disease and its related neuro- cognitive outcomes. ing subcortical brain structures on MRI, ing subcortical brain structures on MRI, consciousness, which are integral to motion, and learning. emotions, Besides genetic factors, we also study the link Besides genetic factors, •Investigating the genetic determinants of cog- Polygenic (genetic) risk profiling can identify groups of individuals who could benefit from the knowl- edge of their probabilistic susceptibility to disease. •Discovering novel genetic variants for high •Discovering novel epigenetic (DNA methyla- Molecular epidemiology of the aging brain our study exemplifies the challenges remain, applications. potential of PRS for clinical such as DNA methyla- between other molecules, of and metabolites with disease proteins, tion, the we assayed For example, the aging brain. metabolites in the collection of all metabolome, the blood of 3,904 men and women at midlife, and identified two novel circulating molecules that conferred a greater risk of future ischemic discoveries may yield newThese insights stroke. into disease mechanisms and lead to the development of new therapeutics. RESEARCH PROJECTS •Discovering DNA sequence variants influenc- Myriam Fornage, PhD Myriam Fornage, Professor in Cardiology Professorship and Johanna Favrot Distinguished The Laurence Throughout our lifetime, our brain changes our brain changes Throughout our lifetime, Our research program investigates the molec- HUMAN GENETICS FOR HUMAN CENTER Beginning more than any other part of our body. changes aging brings about subtle in midlife, and function. chemistry, in brain structure, These changes are detectable by neuroimag- ing techniques such as magnetic resonance imaging (MRI) and are associated with a greater cognitive and functional risk of future stroke, ‘omics’ Novel and death. dementia, impairment, technologies allow us to characterize and quan- tify the sets of biological molecules that make and organisms on a population tissues, up cells, powerful technologies have opened These scale. new toward biomarker discovery for avenues enabling risk prediction and risk stratification, informed preventive and therapeutic interven- brain aging. or reverse, tions to slow, such ular basis of diseases of the aging brain, with In collaboration as stroke and dementia. we researchers in the United States and Europe, apply genome sequencing technologies to iden- tify genes and gene variants that influence risk brain MRI abnor- disease, Alzheimer’s for stroke, and their cardiovascular risk factors. malities, These complex traits are determined by DNA sequence variations occurring in many genes that have small effect sizes and act over long The total number of genetic periods of time. which variants that an individual has inherited, increases their risk of developing a particular ‘polygenic can be measured as their disease, we esti- Using genetic data, risk score (PRS)’. mate these scores to predict whether it is likely that someone will develop a specific disease obesity is a For example, during their lifetime. We major risk factor for stroke and dementia. used a computational algorithm to generate a PRS to predict body mass index (BMI) based on then showed We genotype data. an individual’s that individuals with a PRS in the top 10% of the population have a substantially elevated cardiovascular bariatric surgery, risk of obesity, also showed that differ- We and death. diseases, ences in weight among individuals with different Although PRS emerged as early as childhood. 22 • IMMPACT REPORT risk ofcardiacarrhythmias andSCD. We are been knowntobeassociated withincreased ofthe QT intervalhave gations andshortenings and isausefulclinicalmarkerasbothprolon - population QTintervalvariesacrossindividuals heartbeat.(resting state)inevery Inthegeneral to depolarize(activatedstate)andrepolarize corresponds tothetimetakenbyventricles bers and the QT interval in an electrocardiogram cham- measures theelectricalactivityofheart SCD. Electrocardiography, alsoknownasECG, acteristic/trait (phenotype)thatpredisposesto QT interval, anintermediate observablechar- Instead, wefocus ontheelectrocardiographic diseasesleadingtoSCDintoonegroup.of heart success duetopoolingoftheverydiverseforms susceptibility toSCDdirectlyhavehadlimited studies toidentifygeneticfactorsunderlying for geneticsusceptibilitytoSCD. However, studiesthereisevidence tion- andfamily-level developing VF andSCD. Indeed, frompopula- or geneticfactorsarelikelytoplayarolein clearly showingthatotherenvironmentaland/ disease,those individualswithahistoryofheart risk factorsarepooratpredictingSCD, in even mediately. Mostoftheexistingcardiovascular bydefibrillation im- usually fatalifnotreversed due todisorganizedelectricalsignals. VF is muscles ofventricles(lowerchambersheart) and uncoordinatedcontractionofcardiac SCD isventricularfibrillation(VF), anirregular to SCD, themostcommonprocessunderlying diseasecanlead Although manyformsofheart sign ofanunderlyingcardiovascularcondition. over, inalmosthalfthecases, SCDisthefirst of deathsfromcardiovasculardiseases. More- counts for~15%ofall-causedeathsand~50% United States(~500,000eachyear)andac- cause, istheleadingcauseofdeathsin ofanon-cardiac of rhythm)withoutevidence beatsout to acardiacarrhythmia(whenheart den andanunexpectedpulselessconditiondue public healthproblem. SCD, definedasasud- sudden cardiacdeath(SCD)remainsamajor treatment ofcardiovasculardiseasesingeneral, CENTER FORHUMANGENETICS Despite the progress in the prevention and Despite theprogressinprevention to eachtestelement (50perelement). bycalculatingtheRNA/DNAreadcounts fromtheuniquebarcodesattached elements areevaluated in cardiomyocytecell lines, schematicshownin thebottompanel, where~1000 variant-centeredtest of theseassociationsignals, weareperformingasequencing-based highthroughputenhancerscreen coding sequencevariantsassociatedwith thetrait. As afirststeptowardmolecularcharacterization Nos1ap lossinourmousemodels. QTintervalGWASinhumanshave identifiedalargenumberofnon- heart-restricted expected atweaningfromaheterozygote intercross (-/+×-/+);wearenowevaluating 1 mutantandnormalgene)homozygote mutant(-/-;2genecopies)miceobservedand Assistant Professor Ashish Kapoor, PhD Evaluation of constitutive and heart-restricted •Evaluation ofconstitutiveandheart-restricted •Molecular characterizationofQTinterval RESEARCH PROJECTS impactQTinterval. gene defectsandhowthey these associationstoidentifytheunderlying our workinvolvespinpointingthecausesbehind and theQTintervalingeneralpopulation, associations betweenDNAsequencevariants cells.by ourheart with knowngenetic Starting altering theamountofgeneproductmade altering theformofgeneproductratherby leading toQTintervalvariationdosonotby variation andthatmajorityofDNAchanges many genestogethercontributetoQTinterval we asacommunityhavelearnedsofaristhat to identifyindividualsathighriskforSCD. What potential biomarkers(genesandgeneproducts) serve aspotentialtherapeutic(drug)targetsor interval variation, someofwhichinturncould prospect toidentifythegeneticcausesforQT risk anditsmanagement. Ourstudieshavethe potentially impactourunderstandingofSCD the geneticfactorsforQTintervalvariationwill this variationwiththeaimthatunderstanding interested inidentifyingthegenesthatunderlie arrhythmias andsuddendeathrisk Role ofnon-codingcis-regulatorysequencevariationincardiac variants, genesandtheirmechanisms. GWAS signalstoidentifytheunderlyingcausal •Functional genomicapproachestounder- Research assistant: Alexa Smith, BS LAB MEMBERS ics 26:1811-20, 2017. system development. HumanMolecularGenet- genetic interactioninmouseentericnervous Chakravarti, A. Testing theRetandSema3d Kapoor, A.; Auer, D.R.; Lee, D.; Chatterjee, S.; 88, 2018. sequence variants. GenomeResearch 28:1577- transcription factors, andregulatoryDNA cardiac cis-regulatoryelements, theircognate M.K.; Crawford, G.E.;Chakravarti, A. Human Lee, D.; Kapoor, A.; Safi, A.;Song, L.;Halushka, ences 116:10636-45, 2019. Proceedings oftheNational Academy ofSci- its cardiacgeneexpressionandtheQTinterval. A. MultipleSCN5Avariantenhancersmodulate M.L.; Boerwinkle, E.; Arking, D.E.; Chakravarti Kapoor, A.; Lee, D.; Zhu, L.;Soliman, E.Z.;Grove, KEY PUBLICATIONS cardiac electrophysiology. Nos1ap nullmicetounderstanditsrolein stand cardiacgeneexpressionregulation. copies), heterozygotemutant(-/+; of wildtype(+/+;2normalgene ofnumber top panelshowsachart leads toembryoniclethality. The loss ofNos1apinmousemodels ing Nos1ap, constitutive however vivo, wehavegenerated micelack- characterize Nos1apfunctionin spectively. theaimtofurther With and cellularelectrophysiology, re- regulating QTintervalvariation NOS1AP asacandidategene targeting studieshaveidentified Human geneticandinvitrogene IMMPACT REPORT • • • • 23 : Hoyong Lim, in vivo: Hoyong Lim, KEY PUBLICATIONS autoim- Proatherogenic conditions promote mune Th17 responses Reynolds, Joseph M. Hua Sun, Uk Kim, Young Yeonseok and Teng, Ba-Bie Shino Hanabuchi, PMID: (2014). 153-165 40, Immunity. Chung. 24412615. Atherosclerosis, PCSK9 Deficiency Reduces Apolipoprotein B Secretion and Endothelial Jeffrey Krauss, Ronald M. Dysfunction: Hua Sun, J Lipid Res 59: 207- Teng. and Ba-Bie Chang, T. (This article PMID: 29180444*. 223 (2018). Research Lipid was selected as the Cover for J. as shown below). A critical role of PCSK9 in mediating IL-17-pro- Young T cell responses in hyperlipidemia: ducing Yeonseok Delia Danila, Patrick Kee, Uk Kim, In press. (2019). Teng and Ba-Bie Chung, LAB MEMBERS Research assistant: Xin Li Department of Patrick Kee, Mentorship: Dr. School McGovern Medical Internal Medicine, mice show opposite effect with mice show opposite effect genes associated with atherogenesis and to develop therapy for the treatment of genetic atherosclerotic vascular diseases. 17 RC triple knockout mice to study its effect on atherosclerosis. and atherosclerosis. Taken together, our laboratory is using current together, Taken This diagram displays the role of PCSK9 in atherosclerosis and immune response mediated via IL-17 Under normal lipidemic condition with Tfh cells. and Treg, Th1, including cells and other immune cells, These LDLs do not influence the the hepatocytes produce and secrete normal LDLs. low PCSK9 levels, the he- Under hyperlipidemia condition with increased PCSK9 levels, development of atherosclerosis. which are cholesterol ester and phospholipid patocytes produce increased amounts of modified LDLs, These modified LDLs contribute to the development of atherosclerosis by possibly altering enriched. T cells to increase IL-17 production or via induce T cells programing shifted toward IL-17 producing T cells to influence IL17 Tfh or Treg, Th1, including cytokines production to modulating immune cells, Increased IL17 contributes to the development of atherosclerosis. production. •Using genetic tools and proteomics to identify •Using CRISPR/Cas9 technique to generate IL- Pathogenesis of atherosclerosis and immunity and the and immunity and Pathogenesis of atherosclerosis development of and cell therapies for the treatment of genetic diseases atherosclerotic vascular these triple mice, By deleting PCSK9 from LDb knockout LTp We Th17 cells. decreased IL-17 and reduced regulate the hypothesize that PCSK9 might the which are critical for Th17 cells, function of pathogenesis of atherosclerosis. ATAC-Seq, including RNA-Seq, technologies, to define the cellular and CRISPR/Cas9 RPPA and molecular mechanisms by which proathero- genic factors modulate disease development. Our discovery will provide insight into the understanding of physiological and pathologi- a basis It will provide cal of disease process. to developefficient therapeutic approaches to combat the progression of diseases. RESEARCH PROJECTS inflammation, •The role of PCSK9 in autophagy, Ba-Bie Teng, PhD, FAHA PhD, Teng, Ba-Bie Professor Maury Rubenstein Foundation The Jerry and Professorship in HeartDistinguished Disease Research Atherosclerosis is an inflammatory disease PCSK9 (proprotein convertase subtilisin/ T cells The participation of various helper in the aorta that increases in severity as we includes imbalance lipid The disease age. metabolism that leads to hyperlipidemia and maladaptive immune responses that affect the research focuses on Our arterial vasculature. understanding the development of athero- sclerosis and to elucidate the cross-regulation have We between atherosclerosis and immunity. generated a mouse model that mimics humans with hyperlipidemia by deleting both LDL recep- tor (LDLR) and RNA editing enzyme (Apobec1) These genes (LDb=Ldlr-/-Apobec1-/-). mice Feeding develop as they atherosclerosis age. high-fat diet accelerates their Western on a male Moreover, atherosclerosis development. mice develop atherosclerosis faster and more severely females. than kexin type 9) is a newly identified causative elevated Patients with gene for hyperlipidemia. PCSK9 levels have increased plasma cholesterol We and premature coronary artery disease. delete PCSK9 gene from LDb mice (LTp=Ldlr- showing decreased /-Apobec1-/-Pcsk9-/-), atherosclerosis and apolipoprotein B levels with PCSK9 improved function of endothelial cell. modulates autophagy signaling pathway by inhibiting the degradation of molecules and or- PCSK9 ganelles via autophagosome/lysosome. producing modulates SREBP-1c lipogenesis, more atherogenic LDL containing elevated levels of cholesteryl ester and phospholipids, Further - resulting in increased atherosclerosis. the presence of PCSK9 down regulates more, TGF-β in endothelial cells. the protection role of PCSK9 contributes to atherosclerosis Thus, through its multiple effects on autophagy, hepatic lipid metabolism and cellular immune function in endothelial cells. in the development of atherosclerosis is show that LDb We complex and controversial. atherogenic mice exhibit increased plasma which is associated with interleukin-17 (IL-17), T helper 17 cells (Th17). increased numbers of HUMAN GENETICS FOR HUMAN CENTER 24 • IMMPACT REPORT CENTER FORHUMANGENETICS •Regulation ofproteintranslationbyuORFin RESEARCH PROJECTS associated variants. provide mechanisticunderstandingfordisease order tofinemaptheregulatoryvariantsand annotations withresultsfromgeneticstudies, in and tointegratethesefunctionalgenomics of upstreamOpenReadingFrames(uORFs); RBP binding;toinvestigateregulatoryfunctions noveltoolstosystemicallystudy are todevelop tohumanhealth.relevant Ourimmediategoals these questionsinbiologicalcontextsthatare Our researchprogramfocusesonaddressing that orchestratecriticalbiologicalprocesses?” “Are theretranslationalregulatorynetworks (RBP) cooperateincontrollingtranslation?” as, “Do sequencespecificRNAbinding proteins transcription regulation. We askquestionssuch of factorstoanextentcomplexitysimilar of proteintranslationisregulatedbyanetwork plored. Itremainsunclearwhethertheprocess the post-transcriptionalregulationareleftunex- shaping complexbiologicalprocesses, muchof cooperativity amongsttranscriptionfactorsin intricatenetworksof revealed these efforts oftranscriptionfactorbinding).levels While (i.e. and focusonmeasuringmRNAlevels they profile geneexpressionaretranscript-centric far fromcomplete. Mostpublishedstudiesthat understanding ofgeneregulationis, however, forms thebasisoftheseprocesses. Ourcurrent genesis, precisecontrolofgeneexpression to malignanttransformationduringtumori- cell fatedeterminationduringdevelopment to awiderangeofbiologicalprocesses. From global scalechanges intranslationalregula- in thecontextofstress response, where We expanding thislineofresearch arefurther genetic variantsassociatedwiththisimpact. impact onproteintranslationandidentified ofuORF We asystemicsurvey havereported fromstudiesofahandfuluORFs.supports uORF haslongbeenhypothesizedbased on stress response. Translation regulation by Regulation ofgeneexpressionisfundamental post-translational buffering identifiedatafamily-wiseerrorrate of1%. differences between human andchimpanzee. The bluedatapoints representgenesundersignificant Each datapointonthe plotrepresentsagene, theposition alongeachaxisindicatesfoldexpression oftranslation. totheinter-speciesdifferencesatlevel inter-species differencesattheproteinlevel Post-translationally bufferedgenesareidentified betweenhumanandchimpanzeebycomparingthe •Gene expressionbufferingatthepost-transla- •Identification offunctionalnovelcoding •Using RNAbindingproteinfootprintsequenc- Assistant Professor PhD Wang,Sidney approach toproteintranslation Deciphering theregulatorycode: A functionalgenomics level areoftenassumedtopropagate tothe level tional level. Geneexpressionatthetranscript additional celltypesandtissues. performing ribosomeprofilingexperimentsin in identifyingnovelcodingregionsthrough cell survival. We arealsoexpandingourefforts screens toidentifylocithatareessentialfor this lineofresearchbydesigningknockout remains unknown. We arefollowingupon oftheseloci cal functionandimportance active translationattheseloci, thebiologi- profiling data.evidence of Whileweprovided regions fromasinglecelltypeusingribosome identified7,273novel coding previously regions acrossmultipletissues. We have facilitate researchinthisarea. ageneralandeffectivetoolto to develop known toregulateproteintranslation. We aim protein synthesis. RNAbindingproteinsare ing toinvestigatetranslationalregulationof tion areexpected. Post-doctoral fellow:SandeepBansal LAB MEMBERS primates. GenomeBio.2018Jun27;19(1):83. between convergent proteinexpressionlevels J.K. Post-translationalbufferingleadsto Wang, S.H.; Hsiao, C.J.;Khan, Z.;andPritchard, by ribosomefootprintprofiling. eLife5:e13328. lated openreadingframesinhumansinferred Pritchard, J.K. 2016. Thousands ofnoveltrans- Y.; Engelmann, B.;Stephens, M.;Gilad, Y.; Raj, A.; Wang, S.H.;Shim, H.;Harpak, A.; Li, KEY PUBLICATIONS tissue typesandspecies. we arenowexpandingouranalysistoother howgeneralthisobservationis,to evaluate through post-translationalprocesses. Inorder isoftenbufferedattheproteinlevel level tem, thevariationsobservedattranscript demonstrated that, inourcelllinemodelsys- protein level. Inaseriesofstudies, wehave IMMPACT REPORT • • • • 25 The center recently established a robust recently established a The center Asthma and Sinusitis Retinopathy Diabetic & Autoimmunity Immunology Mucosal Disease Infectious Microbial Injury and COPD Lung Acute Deficiencies Surfactant Lung Degeneration Macular Medicine Regenerative Pulmonary erythematosus. focused on the development program research of of stem cell therapeutics for the treatment lung diseases and for genetic acute and chronic function as deficiencies that affect normal lung diseases, including macular as for major eye well degeneration and diabetic retinopathy. include: interests Research • • • • • • • • PhD Rick Wetsel, & Professor Director Center and Irma MD, PhD J. Müller-Eberhard, Hans Distinguished Chair in Immunology MD Gigli,

he investigators of the Hans J. Müller- J. Müller- of the Hans he investigators for Center Gigli and Irma Eberhard Diseases and Autoimmune Immunology

These studies explore the nature, structure, structure, the nature, These studies explore concert with the molecular studies, the In efforts have these research from Results CENTER FOR CENTER AUTOIMMUNE AND IMMUNOLOGY DISEASES

are examining the molecular, cellular, and genetic cellular, examining the molecular, are autoimmune, allergic, different bases of several and infectious diseases. receptors and function of specific cell membrane and their ligands in modulating immune and inflammatoryresponses. mice with engineered scientists have center’s specific targeted gene mutations or deletions disease. These used as models for human that are facilitated the identification of animal studies have roles that play significant key gene products as the immune system, as well in regulating contributing to the pathogenesis of human disease. therapeutic targets for the identified several of asthma, septic shock, and lupus treatment T 26 • IMMPACT REPORT IMMUNOLOGY AND AUTOIMMUNE DISEASES IMMUNOLOGY ANDAUTOIMMUNE CENTER FOR pathogenesis ofvarious diseasepathologies. numerous biological roles ofcomplementinthe of thesemicehasfacilitated thediscoveryof mouse embryonicstemcells. The generation targeting andhomologousrecombination using receptors havebeenselectivelyablatedby gene complement proteins, regulators, andcell mice inwhichthegenesencodingspecific ment, wehavegeneratednumerous “knock-out” andbiologicalfunctionsofcomple - importance asthma andCOPD. To determinetheoverall a majorcontributortolungdiseases, suchas been discoveredasamajorcauseof AMD and dysregulation ofthecomplementsystemhas these novelcomplementbiologicalfunctions, of thecentralnervoussystem. Inadditionto cells including T-cells, andnormaldevelopment tissue regeneration, polarization ofimmune and viruses. These otherfunctionsinclude biological functionsotherthankillingbacteria inother complement systemisveryimportant inthepastdecade thatthe become evident plasma proteinsandcellularreceptors. Ithas and viralpathogens. Itiscomprisedofover30 being thefirstlineofdefenseagainstbacterial innate immunesystemandiswellknownfor The complementsystemisamajorarmofthe has involvedstudiesofthecomplementsystem. pathological conditions. Muchofthisresearch duringbothnormaland the lungandeye the inflammatoryandimmuneresponsesin moleculesthatmediate delineating thekey yearsfocused on tory hasforthepastseveral of thelungandeye. Accordingly, ourlabora- for theeffectivetreatmentofchronicdiseases ment ofnoveltherapeuticsthatcouldbeused - and repairprocesseshasslowedthedevelop immunity,regarding lungandeye inflammation, paucity ofcellularandmolecularknowledge normal tissuerepairmechanisms. However, the pathologies duetofibrosis, andimpairmentof of healthytissue, establishmentofdebilitating toxic substances, resultinginthedestruction and inflammatoryresponsetopathogenicor often theresultofdysregulationimmune Chronic diseases of the lung and eye are Chronic diseasesofthelungandeye endothelium. elongated cellsdepict activatedB-cellsandpolarized T-cells transmigratethroughthe asthey cells showninbrown withletterE. T-cells andB-cellsshown ingreenandpurple, respectively. The peptides (C3aandC5a)activatesB-cells and polarizes T-cells duringan immuneresponse. Endothelial Model illustratinghowthevascularendothelium onstimulationbythecomplementanaphylatoxin cal SafetyStudyofHumanEmbryonicStem Zsigmond, E.M.; Westenskow, P.D. A Preclini- Domozhirov, A.Y.; Garcia, C.A.; Wetsel, R.A.; Mazzilli, J.L.;Snook, J.D.; Simmons, K.; KEY PUBLICATIONS • •Evaluate thetherapeuticpotentialofgene •Generate “universal donor” embryonicstem •Determine howthefunctionofvascularand RESEARCH PROJECTS deficiency ofsurfactantproteinB. bornwithgenetic gene therapyfornewborns thelium inacutelunginjury, andforcell-based AMD, forregenerationofthedamagedlungepi- derived cellsforrepairofdamagedretinain (hES) andinducedpluripotent(iPS)stemcell investigating thetherapeuticuseofembryonic ofthisoverallresearchprogram,As part weare therapeutic targetforthetreatmentofasthma. and thereforemayprovetobeanexcellent asthma, includingairwayhyperresponsiveness, hallmarksof mediatorofkey is animportant the complementanaphylatoxinpeptideC3a C3a receptorwasdeleted, wediscoveredthat For example, instudiesusingmicewhichthe stem celltherapeuticsfordiseasesofthelungandeye Innate immunology, inflammation, infectiousdiseases, and Hans J. Muller-Eberhard, MD, PhDandIrmaGigli, MDDistinguishedChairinImmunology and Professor andDirectoroftheCenterforImmunology Autoimmune Diseases Rick Wetsel,PhD therapeutics fortreatmentof AMD. hES-retinalpigmentepithelial cells Develop surfactant proteindeficiencies. corrected iPScell-derivedlungcellsfor transplantation. plantable cellsthatwillnotberejectedafter cell linesthatcanbedifferentiatedintotrans- complement duringtheimmuneresponse. lymphatic endothelialcellsareimpactedby Instructor: Pooja Shivshankar,Instructor: PhD Post-doctoral fellow:JohnL. Mazzilli, MD Research scientist:KenSimmons, PhD PhD Mueller-Ortiz,Senior researchscientist:Stacey LAB MEMBERS 118:91-98 (PMID:31862673). macular degeneration. MolImmunol.2020 cells asapotentialtherapyforage-related CD35)-expressing retinalpigmentepithelial Wetsel, RlA. ComplementReceptor1(CR1/ Domozhirov, A.Y.; Garcia, C.A.;Zsigmond, E.M.; Simmons, K.T.; Mazzilli, J.L.;Mueller-Ortiz, S.L.; Cell Res. 2017:18:37-40(PMID:28395800). to humanretinalpigmentepithelialcells. Stem embryonic stemcelllineCR-4:differentiation Derivation andcharacterizationofthehuman S.L.; GarciaC.A.; Wetsel, R.A.;Zsigmond, E.M. Mazzilli, J.L.;Domoshirov, A.Y.; Mueller-Ortiz, 2017: 198:3237-3244(PMID:28275134). cytosolic surveillancepathway. JImmunol. inhibition ofthecyclicdinucleotide-activated in responsetoListeriamonocytogenesby ins, C5aandC3a, suppressIFN-bproduction Y-D.; Wetsel, R.A. The complementanaphylatox- Mueller-Ortiz, S.L.;Calame, D.G.; Shenoi, N.;Li, (PMID: 3159663). 2019: Oct9. doi:10.1089/jop.2019.0039 Macular Degeneration. JOculPharmacol Ther. Cell-Derived RetinalPigmentEpithelialCellsfor IMMPACT REPORT • • • • 27 Karmouty-Quintana, H.; Philip, K.; Chen, N. Y.; Y.; N. K.; Chen, H.; Philip, Karmouty-Quintana, Acero, J.; Davies, F.; G.; Luo, J. Molina, T.; Weng, Johnston, T.; K.; Le, I.;Volcik, Bao; Bunge, L.; Le, M. K.; and Blackburn, H. Eltzschig, Y.; A.; Xia, R. ADORA2B from myeloid Deletion of (2015) R. and pulmonary cells dampens lung fibrosis PMID: 50-60. 29, J. FASEB hypertension. 25318478 LAB MEMBERS Assistant professor: Tingting Weng, PhD PhD Volcik, Senior research scientist: Kelly Chen Research associate: Ning-Yuan Sr. Research scientist: Jose Molina, PhD Graduate student: Josh Ko, Primary type II alveolar epithelial cells isolated from genetically modified mice. the progression of chronic lung disease. IL-6 signaling in pulmonary fibrosis. chronic lung disease. regulation of pulmonary fibrosis and Chronic regulation of pulmonary fibrosis Obstructive Pulmonary Disease. Increased expression (brown color) of proteinases in pulmonary macrophages in mice with pulmonary fibrosis (BLEO). KEY PUBLICATIONS Y.; N. J.; Chen, W.; Davies, T. K.; Mills, Philip, G.; J. Molina, F.; H.; Luo, Karmouty-Quintana, A.; Eltzschig, N.; Guha, J.; Sinha, Amione-Guerra, (2017) HIF1A up- R. M. K.; and Blackburn, H. on alternatively ADORA2B receptor regulates the activated macrophages and contributes to 4745-4758. 31, J. FASEB pulmonary fibrosis. PMID: 12871304 Y; Karmouty- N. Chen, T.; B.; Mills, N. Le, F.; Luo, K.; J.; Philip, G.; Davies, J. H.; Molina, Quintana, K.; and H. Eltzschig, Y.; H.; Xia, A.; Liu, K. Volcik, (2016) Extracellular adenosine R. M. Blackburn, levels with the progression and are associated 30, J. FASEB exacerbation of pulmonary fibrosis. PMID: 26527068 874-883. •Systems Biology approaches to understand Understanding novel mechanistic roles for •Understanding novel mechanistic Examination of the hypoxia as an amplifier of •Examination of the hypoxia Adenosine signaling and the regulation of chronic lung disease and the regulation of chronic lung Adenosine signaling tails in the •Novel regulation of mRNA polyA Michael R. Blackburn, PhD Blackburn, Michael R. UTHealth Academic Officer, Vice President & Chief Executive Sciences, Professor of Biomedical McGovern Distinguished P. Dean and John UTHealth Graduate School Anderson MD Department and Molecular Biology of Biochemistry Vice Chairman, Professor and Disease Distinguished University Chair in Pulmonary Kilroy Sr., William S. Inflammation and remodeling responses are A central hypothesis of my laboratory is that use of genetically modified make extensive We expression on pulmonary macrophages during the progression of pulmonary fibrosis. and chronic lung injury. prominent features of chronic lung diseases pulmonary chronic obstructive such as asthma, and pulmo- pulmonary fibrosis, disease (COPD), Although signaling pathways nary hypertension. associated with the genesis of these diseases about the little is known have been described, signaling pathways that serve to regulate the The major chronic nature of these diseases. goal of my laboratory is to identify pathways that regulate the chronicity of these disorders with the intent of developing novel therapeutic strategies. the signaling molecule adenosine is an amplifier Adenosine of lung inflammation and damage. and it is generated in response to cell damage, is our belief that as adenosine levels increase in the lung they access pathways that serve to promote airway inflammation and remodel- specific Adenosine signals by engaging ing. adenosine receptors on target cells such as airway epithelial fibroblasts, inflammatory cells, Most of the and smooth muscle cells. cells, projects in my laboratory focus on understand- ing the mechanisms by which adenosine signal- ing influences the activities of these cells in the context of lung inflammation and remodeling. mice to examine the role of adenosine signaling This includes knockout in chronic lung disease. mice of components of adenosine metabolism also conduct mechanistic We and signaling. experiments in disease relevant cell types and work extensively with human explanted lungs obtained following lung transplantation here in These translational Medical Center. Texas the approaches help us identify novel strategies for treating chronic lung disease. RESEARCH PROJECTS A2B adenosine receptor •Examining the role of •Investigation of adenosine transport in acute CENTER FOR CENTER AUTOIMMUNE AND IMMUNOLOGY DISEASES 28 • IMMPACT REPORT IMMUNOLOGY AND AUTOIMMUNE DISEASES IMMUNOLOGY ANDAUTOIMMUNE CENTER FOR separating thesinuses fromtheintracranialand of sinuscavitiesand ultimately erosionofbone ties. This trapped mucuscancauseexpansion between thenasalpolypsandwithinsinus cavi- laden withfungalhyphaeandeosinophils with anaccumulationofthickentrapped mucus clinical subtypeofCRSwNPthatisassociated treatment. phenotypes, allowing forpossiblepersonalized has identifiedendotypeswithintheseclinical using clusteranalysisofgeneticinformation 5, andIL-13. However, recentstudybyourlabs expression oftype2cytokinessuchasIL-4, IL- of eosinophils, mast cells, andbasophils with nasalpolyps(CRSwNP)hashighpresence helper celltype1(Th1)cytokines, whileCRS predominance ofneutrophilsandelevated T CRS withoutnasalpolypsischaracterizedby logic profilesoftheinflamedsinustissue. generallybyimmuno- has beensupported polyps (seeimage1). This clinicalclassification defined bytheabsenceorpresenceofnasal tion ofthepatientanddiseasedmucosa. regularly inclinic,- whichallowsperiodicevalua to harvestcriticaldiseasedtissueandareseen often undergosurgeryprovidinganopportunity inflammatory respiratorydiseases. CRSpatients human researchmodelforstudiesinchronic are notcurative. CRSrepresentsanideal rent surgeriesandanti-inflammatoryagents, treatment options, whichtypicallyinvolverecur- unknown aboutitspathophysiology, andcurrent Despite thishealthcareburden, muchremains chronicillnessesinthe UnitedStates.prevalent respiratory diseasesrepresentsomeofthemost asthma. Together, CRSandasthmaaschronic suffering fromCRSoftenarediagnosedwith of over3billiondollars. Inaddition, patients with anannualdirecthealthcaretreatmentcost vatively, 18-22millionphysicianvisitsyearly tion. These symptomsultimatelydrive, conser- and pressure, nasalcongestion, andobstruc - rhinosinusitis (CRS), whichcausesfacialpain Allergic fungalrhinosinusitis(AFRS)isa CRS isclinicallyclassifiedinto2groups Over 40million Americans sufferfromchronic •Molecular signalingthrough respiratory •Characterization ofimmunologicandmolecu - RESEARCH PROJECTS antifungal activityasitrelatestoCRS. that regulateantimicrobialpeptideswith Current studiesarefocusedonthepathways thesinusinflammation.protocols toevaluate upper andlowerairwayinflammationthe of establishingamousemodeleosinophilic response. This hasledustoourrecentinterest from adefectinlocalanti-fungalimmune allergicfungalrhinosinusitismayresult believe response insomeCRSsubtypes. We currently responsible forsignalingintheinflammatory signaling pathway(s)andthefungalcomponent molecular characterizationoffungi-mediated helper cellsinvariousCRSsubtypes. in thefunctionofinnatelymphoidcellsand T interested inthedistributionandultimately immune responseinCRS, wearecurrently and knowndataoftheroleadaptive IL-33. stimulate respiratoryepithelialcellstorelease that fungalantigens, specifically Aspergillus, can 13 inresponsetoIL-33. Interestingly, wefound and representthemajorcelltypeproducingIL- These ILC2expressST2, thereceptorforIL-33, in CRSwNPpatientsrelativetohealthcontrols. nate lymphoidtype2cells(ILC2)preferentially We demonstratedanincreasedpresenceofin- in thediseasedsinonasalmucosaofCRSwNP. firmed thatthereceptorofIL-33isupregulated characteristic ofCRSwithnasalpolyps. We con- orchestrating thetype2immuneresponse linked tothetype2immuneresponse. etin, interleukin(IL)-25andIL-33, havebeen derived cytokines, thymicstromallymphopoi- anti-microbials. Three identifiedepithelialcell through regulationofcytokinesandrelease shown thatepithelialcellsserveanactiverole for sinonasalmucosal. Recentstudieshave first lineofdefenseagainsttheenvironment complications andblindness, respectively. orbital cavitieswhichcanresultinintracranial chronic airwayinflammation Environmental triggersregulatinginnateimmuneresponsesin –HeadandNeckSurgery Otorhinolaryngology Associate Professor, and CenterforImmunology of Autoimmune DiseasesandDepartment Amber Luong, MD, PhD epithelial cellsoffungi aloneandwithother allergic fungalrhinosinusitis. of lar defectscontributingtopathophysiology In addition, mylab isinterestedinthe Given theappreciationofinnateimmunity Our labhasfocusedontheroleofIL-33in Respiratory epithelialcellsrepresentthe Epithelial cells •Clinical characterizationandidentificationof Hua Sun, PhD, Li Yi-Dong LAB MEMBERS Oct;129(10):2230-2235. is PAR2-dependent. Laryngoscope. 2019 of IL-33expressioninchronicrhinosinusitis D.B.; Luong, A.U. Aspergillus fumigatusinduction Dietz, C.J.;Sun, H.; Yao, W.C.; Citardi, M.J.;Corry, Mar;139(3):1061-1064. itis subtypes. J Allergy ClinImmunol, 2017 inflammatory patternsinchronicrhinosinus- distincttype 2 expression profilingreveals S.; Assassi, S.;andLuong, A. Largescalegene J.B.; Dietz, C.J.;Hu, X.;Citardi, M.J.;Fakhri, Tyler, M.A.;Russell, C.B.;Smith, D.E.; Rottman, Immunol. 2014 Aug 134(2):325-331. Th2-Associated 1 Airway Disease.Clin JAllergy Luong A. Airway SurfaceMycosisinChronic Fothergil, A.; Kheradmand, F.; Corry, D.B.; and Tsai, C.L.;Citardi, M.J.;Fakhri, S.;Shaw, J.L.; Porter, P.; Lim, D.J.; Maskatia, Z.K.;Mak, G.; Med.15;188(4):432-9. 2013Aug nusitis withnasalpolyps. AmJRespirCritCare sourceofIL-13inchronicrhinosi- important IL-33-responsive innatelymphoidcellsarean Corry, D.B.; Kheradmand, F.; Liu, Y.J.; Luong, A. Shaw, J.L.;Fakhri, S.;Citardi, M.J.;Porter, P.C.; Science.16;341(6147):792-6. 2013Aug allergic responsesthrough Toll-like receptor4. Cleavage offibrinogenbyproteinaseselicits C.J.; Luong, A.; Kheradmand, F.; Corry, D.B. Roberts, L.;Song, L.Z.;Knight, J.M.;Creighton, Millien, V.O.; Lu, W.; Shaw, J.; Yuan, X.;Mak, G.; KEY PUBLICATIONS nasal cavityofCRSwNP patient. Nasal polypsseenby nasalendoscopywithin immune response. ing and/ormaintainingthecharacteristic Th2 environmental triggersresponsibleforinitiat- biomarkers forCRSsubtypes. polyps Nasal IMMPACT REPORT • • • • 29 Doi.10.1089/jop. 2019. Doi.10.1089/jop. CRISPR/Cas9 -mediated gene editing for the production of novel animal models. CR-4 human ES cell-derived retinal pigment epithelial cells KEY PUBLICATIONS K.; Simmons, J.D.; J.L.; Snook, Mazzilli, R.A.; Zsig- Wetsel, C.A.; Garcia, A.Y.; Domozhirov, A Preclinical P.D. Westenskow, and M.; E. mond, Safety Study of Human ES Cell-Derived RPE Cells Degeneration J. of Macular Treatment for the Ocul. Pharm Ther. R.A.; and Wetsel, J.L.; Mazzilli, A.Y.; Domozhirov, M.; Generation of CDMLe012-A-1: E. Zsigmond, Turner’s A Pluripotent Human ES Cell Model of 2019. Stem Cell Res. 39:101508, Syndrome. LAB MEMBERS Aleksey Domozhirov Senior research associate: MD Post-doctoral fellow: John Mazzilli, RESEARCH PROJECT Age-Related Macular Therapy for Stem Cell Degeneration lines, including human ES cells approved for including human ES cells approved lines, NIH-funded research. in the production of knock-out mice when using ES cells derived at the facility. 23%). cells and MEF feeder layer cells. cell lines. preservation of mouse ES cells. preservation of mouse ES cells. eggs. eggs. eggs. of knock-out and knock-in mice. the production of transgenic animal models. the production of transgenic 100% success rate in re-derivation of mice. •100% success rate in re-derivation of mice. •Derivation of over 20 mouse and human cell •100% success rate of germline transmission Accomplishments: •Consistently high transgenic rates (average •Availability of germline-competent mouse ES •Derivation of novel mouse ES cells and other Gene targeting, selection, expansion, cryo- expansion, selection, •Gene targeting, •Cryopreservation of fertilized mouse and rat •Re-derivation of mice and rats from fertilized Microinjection of ES cells for the production •Microinjection of ES cells for Transgenic and stem cells core facility and stem cells core Transgenic RESEARCH SERVICES editing. •CRISPR/Cas9-mediated genome clones for YAC BAC or •Microinjection of DNA, Eva M. Zsigmond, PhD Zsigmond, Eva M. Associate Professor Facility and Stem Cells Core Transgenic Director, The Transgenic and Stem Cells Core Facility and Stem Cells Transgenic The - cryopreserva In addition to the production, The embryonic stem (ES) cell lines derived Our laboratory also has generated human ES provides a unique service to the UTHealth scientific community by generating animal models of specific human diseases in order to The laboratory was develop treatments. novel it established in 1998 and since that time, has generated more than 850 new transgenic, knock-out and knock-in animal models for for as well as investigators from UTHealth, scientists from numerous other academic institutions. tion and re-derivation of genetically-engineered also the services of the facility mice and rats, derivation of new cell include gene targeting, and technical support in different aspects lines, and stem cell culture, of animal microsurgery, cells research. in the Core Laboratory are highly effective for In a studies involving cellular differentiation. is using our laboratory current research project, human ES cell-derived retinal pigment epithelial (RPE) cells as a therapeutic strategy for the treatment of age-related macular degeneration ARMD is a leading In the United States, (ARMD). The aim of our study is to cause of blindness. use RPE cells derived from human ES cells in a clinical trial of sub-retinal transplantation ARMD for the reversal of into patients with the visual loss associated with the disease. functional human RPE cells have derived We in our laboratory and have tested the efficacy In and safety of these cells in animal models. we are examining preparation of clinical trials, the long-term viability of the transplanted cells and we will ARMD, in murine animal models of generate transplantable human RPE cells in a GMP-certified facility. cells with stable deletion of an X-chromosome. This cell line represents a pluripotent stem cell model to study the disease mechanisms one of the most common syndrome, Turner’s of genetic abnormalities seen in female embryos. CENTER FOR CENTER AUTOIMMUNE AND IMMUNOLOGY DISEASES 30 • IMMPACT REPORT T muscle disease anddiabetes? • utilization indiabetes? • dysfunction? inflammation implicatedin metabolic • therapeutic purposes? • contribute todiabetesandcancerprogression? • progenitors underliediabetesdevelopment? • following: addressed by thecenter’s facultyincludethe clinical specimens.Thespecificquestionsbeing interrogated inanimalmodelsandstudies on that leadtophysiologicalabnormalitiesare being protein homeostasis, andcellfatedetermination metabolism, vascular function,cellsignaling, associated changesinbrainactivity, energy cancer. Mechanisms ofaging, stress, andobesity- vascular insufficiencies, neurodegeneration, and including type-2diabetes,musclewasting, CENTER FORMETABOLIC AND DEGENERATIVE DISEASES What vascular genescan betargetedtotreat How dostress hormones regulate energy How isangiogenesis, fibrosis, and Can cellsofadiposetissuebetargetedfor How doadipocyte-derived fattyacids How doesreplicative senescenceofadipocyte investigate aging-associateddiseases, Metabolic andDegenerative Diseases he eightlaboratoriesoftheCenterfor in Metabolic Disease Research Harry E.Bovay, Jr. DistinguishedUniversity Chair Center Director Professor &Associate Mikhail Kolonin, PhD metabolic anddegenerative diseases. their discoveries forthebenefitofpatientswith epidemiologists, andclinicianstotranslate members collaboratewithpathologists, productivity andinnovation. Thecenter’s promotes research synergy, thereby increasing Collaboration amongthecenter’s laboratories and post-traumaticstress disorder? • cause neurodegeneration? • neurodegenerative diseases? • homeostasis indiabetes? • liver disease andcancer? • control the body’s energybalance? • How doesstress promote Alzheimer’s disease How ofcellularhomeostasis doesdisruption What are thefunctionsofgenesmutatedin How doesthebraincontrol glucose How doesthecircadian clockprotect against How doesthebrainandcircadian clock IMMPACT REPORT • • • • 31 2019 health, and targeting in disease. health, disease progenitors and its role in metabolic of lipids driving cancer progression. Aging-associated exhaustion of adipocyte. exhaustion of adipocyte. Aging-associated • as the source • Cancer-associated adipocytes KEY PUBLICATIONS The role of adipose stroma in prostate cancer J. Kolonin M.G.; DiGiovanni aggressiveness. Androl Urol. Transl CRISPR/Cas9-based dystrophin restoration re- veals a novel role for dystrophin in bioenerget- ics and stress resistance of muscle progenitors. M.A.; Hall, D.; J.; Danila, Wu, X.; Mu, P.R.; Matre, J. R.; Huard, M.G.; Darabi, Kolonin, Adipose stromal cell targeting suppresses pros- tate cancer epithelial-mesenchymal transition A.; S.; Saha, Ahn, F.; Su, and chemoresistance. 2019 Oncogene. M.G. J.; Kolonin, DiGiovanni, LAB MEMBERS Alexis Daquinag, Senior research scientists: Zhanguo Gao Research scientist: Fei Su Graduate student: Shraddha Subramanian Research assistant: Cale Fussell Changes in subcellular localization of fatty acid transporter CD36 (red) in adipocytes treated with fatty acids (left) or induced to undergo lipolysis (right). Adipocyte progenitor cells: Dysfunction in disease and aging cells: Dysfunction in disease and Adipocyte progenitor and metastasis and to chemotherapy resistance are also ap- We assess them as a drug target. Ap- Therapeutic ASC as a New plying ablation of dystrophy treat- proach to Duchenne muscular In collaboration with bariatric surgeons, ment. targets human we recently showed that D-WAT treatment Our reports that D-WAT indicate ASCs. leads to generation of ASCs, spares brown fat brown adipocytes and enables a short-term our recent data in- However, metabolic benefit. dicate the importance of maintaining functional fat cell num- As we age, ASCs for healthy aging. bers decrease and the deficient fat tissue fails which start spilling to effectively absorb lipids, This can cause inflammation into other organs. and metabolic disorders accounting for cancer Our experiments and organ failure in the elderly. in animal models suggest that adipocytes run potential with ASCs lose replicative out because age due to telomere shortening and become which is accelerated by obesity. ‘exhausted,’ Understanding the mechanisms and function of fatty acid transport through CD36 in the context of type-2 diabetes and cancer is our Another recent research most recent pursuit. direction is focused on the role of inflammatory signaling and fat tissue remodeling in metabolic response to anti-diabetes drugs. RESEARCH PROJECTS function in Adipocyte progenitors: lineages, • Mikhail Kolonin, PhD Mikhail Kolonin, Diseases Metabolic and Degenerative Center for Professor & Director, Research Chair in Metabolic Disease Distinguished University Jr. Bovay, Harry E. My laboratory investigates mechanisms un- A micrograph showing localization of adipose stromal cells (green) Nuclei are blue. A: adipocytes. around blood vessels (red) in fat tissue. type-2 including derlying aging-related diseases, We and cancer. muscle degeneration, diabetes, are focusing on the role of fat (adipose) tissue While white in the context of these pathologies. adipocytes store lipids and release them in brown adipocytes burn times of energy scarcity, obesity, In lipids off to keep the body warm. overgrown white fat becomes inefficient in hold- cardiovas- hence causing diabetes, ing lipids, active In contrast, and cancer. cular diseases, brown fat can prevent the onset of metabolic are Both white and brown adipocytes disease. their and continuously replaced as we age, pools in fat tissue are maintained by adipose increased numbers In obesity, stem cells (ASCs). Our laboratory ASCs are generated. of white fat ASCs has discovered that tumors recruit these no drugs Currently, that fuel cancer progression. targeting cells in fat tissue for obesity or cancer of advantage Taking indications are available. we have our expertise in targeted therapeutics, developedthe first experimental drug (D-WAT) Our publications demonstrate ASCs. targeting prevents obesity and suppresses that D-WAT are now using this We tumor growth in mice. experimental drug to investigate the mechanism ASC promote cancer progression through which METABOLIC AND DEGENERATIVE DISEASES DEGENERATIVE AND FOR METABOLIC CENTER 32 • IMMPACT REPORT treat insulinresistanceandtype2diabetes. whether SIK1mightbeausefuldrugtargetto utilizationintype2diabetesand muscle energy understand howSIK1contributestoimpaired enzyme calledSIK1. One of ourmajoraimsisto induced byhormoneactivityinmuscleisan curs atthemolecularlevel. Oneoftheproteins cell activity, andweaimtoidentifyhowthatoc- mones, likeadrenaline, stimulatemusclestem that intracellularpathwaysactivatedbyhor- muscle stemcellstobeactivated. We found metabolism andpromotingthecapacityof healthy agingbymaintainingmuscle to ameliorateinsulinresistanceandpromote muscle stemcellfunction. The overallgoal is targets toimprovemusclemetabolismand cells inhopesofidentifyingnoveltherapeutic in matureskeletalmuscleandstem responsible forthelossofmusclemass. muscle stemcellactivityisthoughttobepartly well asmetabolism. Inagingindividuals, lossof declines, causingbothdisruptionsinmobilityas with type2diabetes. Duringaging, musclemass inpeople ing factortohighbloodsugarlevels Muscle insulinresistanceisamajorcontribut- uptake ofsugarfromthebloodafterameal. is responsiblefor~85%ofinsulin-induced tain bodytemperature. Infact, skeletalmuscle mobility, andgenerationofheattohelpmain- of energy, maintenanceofspinestabilityand forutilizationandstorage muscle isimportant lifting objectsandescapingpredators, skeletal muscle tocontractandperformworksuchas addition tothemajorfunctionofskeletal 40% ofbodymassinhealthyindividuals. In CENTER FORMETABOLIC AND DEGENERATIVE DISEASES Our labstudieshormone-activatedpathways Skeletal musclecomprisesapproximately H.; O’Brien W.; Xu, Y.; Mangieri, L.R.;Zhu, Y.; Kim, E.R.;Fan, S.; Akhmedov, D.; Syn, K.;Lim, Mol CellBiol. 201737(9):e00584-16. temporal stimulationofcyclic AMP signaling. Gs-DREADD knock-inmicefortissue-specific, Rajendran, K.;Rossi, M.; Wess, J.;Berdeaux, R. Akhmedov, D.; Mendoza-Rodriguez, M.G.; KEY PUBLICATIONS •Understand howdifferenthormonalpathways •Study ofhowcAMPsignalingregulatesskel- •Identification oftherolesSIK1inmuscle RESEARCH PROJECTS new musclefibers. new activated pathwaysandstudytheeffectsofthoseonmuscleregeneration andregrowthof not actonanyotherreceptorsnormallyexpressedinthemuscle. Inthisway, wecanmimic hormone- muscle cells. This receptorallowsustostimulatethesamehormonalpathwayswithadrugthatdoes regrow. Inthisexperimental model, formed weexpressedareceptor(stainedingreen)thenewly aged muscle. Blue showsallcellsinthetissuesection. B) Two dayslater, musclesareformedand new become activatedtogrowanddivide. The redstainrecognizestheproliferatingcellswithindam- Characterization ofregeneratingskeletalmuscle. A) Three daysafter muscleinjury, musclestemcells signaling pathways Regulation ofmusclemetabolismandregenerationbycellular Associate Professor Rebecca Berdeaux, PhD and famine. storage inskeletalmuscletimesoffeast utilizationand collaborate toregulateenergy etal musclestemcellactivityinaging. glucose metabolisminobesity. Medical student: Gonzalez Victor Mahmoud Farhan assistants: AlexanderAmbrocik,Research Research scientist:Dmitry Akhmedov LAB MEMBERS Metab, 5:34-46. *, equalcontribution. 1 promotesinsulinresistanceinobesity. Mol (2016) Skeletalmusclesaltinduciblekinase Berglund, E.D.; Justice, N.J.;andBerdeaux, R. Rodriguez, M.G.;Rivera-Molina, Y.; Gibson, M.; Akhmedov, D.; Rajendran, K.;Mendoza- Nixon, R.;*Fu, M.;*Stewart-Fitzgibbon, J.;* Insight 20172(14):93367. expenditurebyincreasingO2supply.energy JCI adrenergic receptorscontributetodiet-induced K.; Berdeaux, R.; Tong, Q. Redbloodcellb- Lee, C.C.;Chung, Y.; Xia, Y.; Xu, Y.; Li, F.; Sun, IMMPACT REPORT • • • • 33 hepatocellular carcinoma” Fekry, B.; Ribas Fekry, hepatocellular carcinoma” A.M.T.; C.; Mohamed, A.; Baumgartner, Latre, M.; and Younes, F.M.; M.G.; Sladek, Kolonin, 2019, Oct. Cancer Research K.L. Eckel-Mahan, (Epub ahead of print). “Incompatibility of the circadian protein BMAL1 - Baha and HNF4α in hepatocellular carcinoma” BaumgartAleix Ribas-Latre; Corrine - ran Fekry; Deans; Christopher Kwok; ner; Jonathan R. Pooja Patel; Loning Fu; Rebecca Berdeaux; Wang; Kolonin; Sidney H. Kai Sun; Mikhail G. Sladek; and Kristin Frances M. Yoo; Seung-Hee 2018; Nature Communications Eckel-Mahan. 9: 4349. “Rosiglitazone Reverses High Fat Diet-Induced and Fat, Changes in BMAL1 Function in Muscle, B.; Fekry, A.; Ribas Latre, Tissue in Mice” Liver S.; Sun, C.; Shivshankar, C.; Bamgarner, Kwok, International K. Z.; and Eckel-Mahan, K.; Chen, of Obesity 2018 May 24. Journal LAB MEMBERS Aleix Ribas Post-doctoral fellows: Baharan Fekry, and Rafael Bravo Santos Latre, Drunen Van Graduate student: Rachel Abnormally large adipocytes in the visceral fat of mice harboring a genetic disruption of the circadian clock (top= normal adipocytes; bottom=adipocytes of Clock knockout mice). in human adipose tissue. liver cancer. leads to metabolic disease. leads to metabolic disease. In addition to metabolic diseases, such as such In addition to metabolic diseases, Circadian clocks in health and disease Circadian clocks Kristin Eckel-Mahan, PhD Kristin Eckel-Mahan, Assistant Professor KEY PUBLICATIONS “HNF4α-deficient fatty liver provides a permissive environment for sex-independent • Understanding the role of the circadian clock • Mechanisms linking circadian disruption to that become insulin resistant under these that become insulin resistant we hypothesize that Thus, feeding conditions. gain in parta high-fat diet induces weight by the circadian rhythms of normally “misaligning” vs. tissues, highly insulin-sensitive peripheral Clock misalignment is thought the brain clock. to be involved with several metabolic disorders, we have In addition, including type 2 diabetes. discovered a new circadian mechanism of pre-adipocyte proliferation in adipose tissue, which we hypothesize controls both the size and health of adipose tissue stores over the lifetime of an organism. has circadian disruption obesity and diabetes, have identified We also been linked to cancer. that a nuclear receptor with circadian activity gets altered in the context of specific liver to restore the circadian Attempts cancers. function in these cells causes cell death and using this infor- are We impairs tumor growth. mation to determine whether these subsets of liver cancers might be responsive to particular circadian manipulations not previously thought of as being applicable to hepatic tumorigenesis. RESEARCH PROJECTS • Mechanisms by which circadian disruption Loss of circadian HNF4α activity in the liver (which can also occur under conditions of chronic high-fat feeding) combined with prolonged high-fat diet results in hepatocellular (left liver= carcinoma in male and female mice. Hnf4a knockout mice fed low-fat diet; right= Hnf4a knockout mice fed low-fat diet) The goals of my lab center on the role of While the central clock of the brain is pre- Our lab and others have shown that nutrient METABOLIC AND DEGENERATIVE DISEASES DEGENERATIVE AND FOR METABOLIC CENTER The the circadian clock in health and disease. circadian clock in an exquisite internal time- keeping system present in all cells of our body rhythms in physiology and that drives 24-hr. of our daily Examples tissue-specific function. food rhythms include the sleep/wake cycle, and hormone internal body temperature, intake, internal clock adapts to and is This secretion. rotation of the earth on aligned with the 24-hr. Recent evidence from large epide- its axis. miological studies (which is well supported by carefully controlled experiments in other organisms) reveals that chronic circadian dis- ruption increases our risk of several diseases. Examples of circadian disruption include travel a night shift working across time zones (jet-lag), light and or rotating shifts (“social jet lag”), contamination by white and blue light sources. lead some clock gene mutations In addition, When the circadian clock is to sleep disorders. several disrupted genetically or environmentally, acceler- including deleterious outcomes result, We and metabolic disease. cancer, ated aging, are trying to understand why circadian disrup- tion produces these effects. circadian oscilla- dominantly controlled by light, tions in peripheral organs are heavily controlled (“time-givers”) such as by other zeitgebers Poor quality nutrients as well as food food. intake at the wrong time can impair circadian increasing the communications across the body, such as obesity and risk of metabolic diseases, Our current experiments include those diabetes. are most designed to reveal which zeitgebers important for tissue-specific clock function and the mechanisms by which tissue-specific clocks protect against metabolic disease. timing and quality have a strong influence on such as the clocks peripheral circadian clocks, Over- and adipose tissue. muscle, of the liver, high-fat diet can consumption of an unhealthy, cause substantial disruption of the circadian clock in normally highly insulin sensitive tissues 34 • IMMPACT REPORT CENTER FORMETABOLIC AND DEGENERATIVE DISEASES effects ofstressondisease progression. Our feelings ofstress, andalsoblockthenegative drugtargets thatcanbothalleviate new stress inourownlives, itwillperhapsidentify ofcontrolling inform usastotheimportance mechanisms thatdrivediseasewillnotonly The identificationofspecificstress-related andnegativelyaffectourhealth.physiology way ourbrainsfunctiontoalterthebodies’ mechanisms bywhichstresschangesthe behaviors. controlourthoughtsand understand howthey neurons andneuralcircuitsaswetryto renaissance duetotheabilitymanipulate of neuroscienceiscurrentlyexperiencinga our abilitytoanswerthesequestions;thefield genetictoolsthatwillimprove new developing threatening situations. We arealsoconstantly it isinvolvedwhenweencounterstressor typeofcellthatweidentifiedandhow a new do. A secondprojectisattempting todescribe as wellwhywemakethedecisionsthat the stressesinourlivesaffectwaywemove, addiction toobesity. We are interestedinhow making, whichisaproblemindiseasesfrom ofthecircuitrythatcontrolsdecision- a part make thechoicesweandareintimately circuits areinvolvedindeterminingwhywe altering ourabilitytomove. However, thesame as Parkinson’s disease, occur, dramatically When thesecircuitsmalfunction, diseasessuch connect tocircuitsthatcontrolmovement. circuits bywhichstressresponsiveneurons with motorcontrolcircuitry. We discoverednew understanding howstresspathwaysinteract One specificprojectisnowfocusedon neurons thatoccursin Alzheimer’s disease. diabetes, toage-dependentdegenerationof conditions, frommetabolicdiseaseslike negatively impactotherseeminglyunrelated inthestresshormone,elevations cortisol, can the consequencesofchronicstress, including common sufferedbyourpopulation. Inaddition, related diseasesthatareamongthemost We areactivelyinvestigatingthebiological High stresscausesanxiety-anddepression- Assistant Professor Nicholas Justice, PhD Stress signalinginpsychiatricanddegenerativedisease N.J. (2018). Paraventricular hypothalamicand Jiang, Z.;Beierlein, M.;Chan, C.S.; andJustice, Hunt, A.J.; Dasgupta, R.;Rajamanickam, S.; Stress 8, 127–133. stress and Alzheimer’s disease. Neurobiol. Justice, N.J. (2018). The relationship between of Stress available online August 17, 2019, Neurobiology Hypothalamus CoordinatesStressResponses., signaling intheParaventricularNucleusof Jiang, Z.;Rajamanickam, S.;Justice, N.J.*CRF KEY PUBLICATIONS •Understanding stressandstress-related •Searching forbiomarkersthatpredictPTSDin •Defining aneuralcircuitthatcontrolsand •Searching forgeneticandenvironmental •Investigating whywerespondtostresstheway •Defining theanatomyofneuronalcircuitsthat RESEARCH PROJECTS before acceptingafacultypositionattheIMM. Hui ZhengattheHuffingtonCenteron Aging, influence ofstressin Alzheimer’s Diseasewith at BaylorCollegeofMedicinestudyingthe stress. ImovedtoHoustonasaninstructor mechanisms bywhichthebodyrespondsto At theSalkInstitute, Ilearnedthemolecular under Wylie Vale, myfirstHoustonianmentor. Diego forpost-doctoraltrainingandstudied Nung Jan. ImovedtotheSalkInstituteinSan Francisco (UCSF), andstudiedinthelabof Yuh Neuroscience attheUniversityofCalifornia, San andaPh.D.of CaliforniaatBerkeley in disease. the goalofpreventing, slowing, orcuring and howwecanusethatknowledgetomeet circuits thatrespondtostressimpactdisease, to understandhowtheneuralandhormonal in patients. day The Justicelabisworkingevery eliminate metabolicanddegenerativediseases long-term goalistoprevent, improve, or progression. diseases influence Alzheimer’s Disease recently traumatizedpatients coordinates stresshormonerelease. sensitivity. factors thatcausestressresilienceand that wedo. respond tostress. I obtainedaB.A. fromtheUniversity emotions. the amygdala, thebrainareathatcontrols our patient showsthatamyloid plaquesformin Human braintissuefroman Alzheimer’s from hidingtorunningawayapredator. animalswitches One exampleiswhenaprey function ofcircuitsthatcontrolourmovement. peptide CRF(green), whichcausesashiftinthe basal gangliaexpressreceptorsforthestress “Stress Responsiveneurons.” Neuronsinthe Research technician:Jonathan Tao Rajamanickam, PhD Post-doctoral fellow:Shivakumar LAB MEMBERS Nucleus. J. 38, Neurosci. 1874–1890. Signaling intheHypothalamicParaventricular (2018). Factor LocalCorticotropin-Releasing Jiang, Z.;Rajamanickam, S.;andJustice, N.J. globus pallidus. Brain Struct. Funct amygdalar CRFneuronssynapseintheexternal IMMPACT REPORT • • • • 35 Vascular cells in culture. Microscopic image cells in culture. Vascular they where of vascular cells grown in culture, spontaneously form tube-like structures called ‘angiogen- phenomenon is called This sprouts. which is the process by which new blood esis,’ vessels are formed. Skeletal muscle cross-section view. Skeletal muscle cross-section view. Immunohistology image of a skeletal muscle cross-section showing different types of dark) decorated with red, myofibrils (green, blood vessels (yellow). growth and diabetic retinopathy. recovery in peripheral arterial disease, recovery in peripheral arterial disease, and obesity, Duchenne muscular dystrophy, diabetes. lism, vascularization, mass, and fitness by mass, vascularization, lism, nuclear receptors. KEY PUBLICATIONS Kim, Y.; Yao, S.R.; M.K.; Setijono, I.K.; Park, Vila, S.W.; Choi, V.; S.; Narkar, Choi, P.M.; H.; Badin, A M.S. S.J.; Song, C.; Song, J.; Moro, Chung, muscle-specific UBE2O/AMPKα2 axis promotes insulin resistance and metabolic syndrome in 2019. pii: 128269, 4(13). JCI Insight. obesity. E.J.; Sopariwala, Milliman, V.; Yadav, N.; Likhite, M.; Sheth, N.P.; S.; Narayana, Lorca, D.H.; of Loss V. Narkar, V.; E.L.; Giguère, Reineke, Alpha Facilitates Estrogen-Related Receptor Mol Cell Biol. Angiogenesis in Endothelial Cells. 2019. pii: e00411-18, 39(5). Likhite, P.M.; Badin, V.; Yadav, D.H.; Sopariwala, E.R.; I.K.; Kim, Vila, S.; M.; Lorca, N.; Sheth, G.G.; Narkar, M.S.; Rodney, Q.; Song, Tong, Long-term PGC1β overexpression leads to V.A. autophagy and muscle wasting. Sci apoptosis, 2017. 7(1):10237, Rep. LAB MEMBERS Neah Post-doctoral fellows: Danesh Sopariwala, Likhite Nitya Research assistants: Meghna Seth, Lisa Lin Narayana, Visiting Hygor Araujo fellows: Vikas Yadav, •Role of nuclear receptors in blood vessel Nuclear receptor target discovery for muscle •Nuclear receptor target discovery Gene regulation in metabolic-vascular syndromes Gene regulation in RESEARCH PROJECTS of muscle metabo- regulation •Transcriptional Vihang Narkar, PhD Vihang Narkar, Associate Professor Professorship in Foundation Distinguished Josephine Hamman George and Mary Research Cardiovascular Our laboratory broadly studies transcrip- we also have uncovered On the other hand, tional regulation of metabolic and vascular homeostasis using nuclear receptors as model we are investigat- Currently, signaling molecules. ing the cellular and physiological functions of estrogen-related orphan nuclear receptors (e.g. PGC1’s). receptors) and their co-regulators (e.g. including use a wide-ranging approach, We disease murine genetically engineered mice, analy- high-throughput gene expression models, ChIP-sequencing), RNA-sequencing, sis (e.g. and in vitro systems cell signal, pharmacology, These tools are being used to in our studies. in (I) and PGC1’s investigate the role of ERR’s gene such as genome-wide cellular processes, and mitochondrial biogenesis, orchestration, angiogenesis; (II) physiological phenomenon, such as exercise adaptation and whole-body metabolism; as well as (III) diseases such as peripheral arterial disease, obesity/diabetes, work Our ongoing and muscular dystrophies. has uncovered the therapeutic role of estrogen- via metabolic and related receptors (ERR’s) angiogenic regulation in peripheral arterial and in Duchenne muscular disease (PAD), our studies on Similarly, dystrophy (DMD). peroxisome proliferator activator receptor delta have yielded insights in to exercise (PPAR-delta) mimicking cellular mechanisms that can be protect against harnessed to boost metabolism, obesity and prevent diabetes. the detrimental role of nuclear receptor co-ac- and muscle degenera- tivator PGC1-beta in PAD apoptotic, tion via regulation of anti-angiogenic, Our work spanning and autophagic pathways. the area of metabolic vascular syndromes that diabetes and its cardiovascular include obesity, complications has been published in journals Cell Reports, Cell Metabolism, including Cell, eLife and Nature Com- Research, Circulation munications. METABOLIC AND DEGENERATIVE DISEASES DEGENERATIVE AND FOR METABOLIC CENTER 36 • IMMPACT REPORT many novelproteins that translocalizeontolipid them bymassspectrometry. Excitingly, wefound teins fromthebrown fattissuesandanalyzed vironment tosustainmetabolicflexibility. ultimately leadingahighlyunfavorablemicroen - which acceleratesfibrosisandinflammation, collagen 6α3andproducesendotrophin pre-existing unhealthyadiposetissue, itdigests hypoxia. Ontheother hand, inthecontextof thepathologicalconditionscausedby relieving esis incombinationwith VEGF-A andleptin, thus collagenous proteinsandstimulatesangiogen- at earlystagesofobesity, MT1-MMPcleaves metabolic contextdependent:Ontheonehand, regulation ofECMflexibilitybyMT1-MMPisalso note, ourrecent research suggeststhatthe ofextracellularmatrix(ECM).of thelevels Of MMP (MMP14)playsacriticalroleinregulation cally dysfunctionaladiposetissueandMT1- found fibrosisisthehallmarkinmetaboli- obese anddiabeticanimalmodels. Indeed, we in of adiposetissueremodelingatotherlevels ing dysfunctionaladipocytes. leads toimprovementsinmetabolismbyablat- expanded adiposetissue, antiangiogenicaction white adipocytes. Incontrast, inpathologically ization andinducinga “browning” phenotype in metabolically beneficialbyimprovingvascular- stage ofobesitydevelopment, angiogenesisis and metaboliccontextdependent:attheearly in whiteadiposetissuecouldbedichotomous demonstrated that VEGF-A inducedangiogenesis adipose tissue. Moreimportantly, wefurther leads tolocalfibrosisandinflammationin induction istheinitialstepwhichultimately fat padsarefrequentlyhypoxicandHIF1α resistance. significance inhumanobesityandinsulin pinpoints themascriticalfactorswithclinical and remodeling duringobesitydevelopment factors tothedynamicsofadiposetissue essential contributionsofadipocyte-derived CENTER FORMETABOLIC AND DEGENERATIVE DISEASES Most recently, wepurifiedlipiddropletpro- We exploredthefine-tunedregulation further In thepastyears, wediscoveredthatobese Research inourlaboratoryexaminesthe •Dynamics oflipiddropletsandthemetabolic ofadiposetissuefibrosis bynovel •Reversibility •Sympathetic innervationduringadiposetissue •Hypoxia-induced pathologicalchangesin RESEARCH PROJECTS UCP-1. mechanism(s) bywhichCes3up-regulates molecule UCP-1. We arenowinvestigatethe cold exposurebyregulatingthethermogenic that Ces3isinvolvedinthermogenesisduring which possesseslipolyticactivity. We found Carboxyl esterase3(Ces3)isoneofthem droplets inresponsetosympatheticactivation. and diabetes Targeting adiposetissueremodelingfortreatmentofobesity Assistant Professor Kai Sun, MD, PhD stimulation (Yang etal. Diabetes, 2019). indicates co-localizationofCes3withlipid dropletproteinmarkerperilipin1inresponsetocold molecules locateinER, significantamountstargetlipiddropletsupon coldexposure. Theyellowcolor antibodies onwhiteadiposetissueofhighfat-dietfedmiceuponcoldexposure. While mostofCes3 Ces3 Translocates ontoLipidDroplets:Co-immunostainingwithα-Ces3(red)and-Perilipin1(green) outcomes. anti-fibrotic therapies. healthy expansion. adipose tissue. PhD; HyunhoLee, PhD Post-doctoral fellows:XinLi, MD, PhD;Li Yang, LAB MEMBERS sue.Exp. 2019Feb13;(144). JVis Blood Vessels in andNerveFibers Adipose - Tis Li, X.;Mao, Z.; Yang, L.;Sun, K. Co-staining esis. Diabetes. 2019Jun;68(6):1178-1196. Signaling-Stimulated Thermogen- β-Adrenergic K. A UniqueRoleofCarboxylesterase 3(Ces3)in Yang, L.;Li, X.; Tang, H.;Gao, Z.;Zhang, K.;Sun, 2018 Aug; 20. doi:10.1128/MCB.00242-18. the SympatheticNervousSystem. MolCellBiol. Expenditurevia Promotes Energy Activation of in AdiposeTissue of VEGF-A Overexpression Tong, Q.;Gu, X.;Kolonin, M.G.;Sun, K. Transient Zhao, Y.S.; Li, X.; Yang, L.;Eckel-Mahan, K.; KEY PUBLICATIONS IMMPACT REPORT • • • • 37 Mangieri, L.R.; Jiang, Z.; Lu, Y.; Xu, Y.; Cassidy, Cassidy, Y.; Xu, Y.; Z.; Lu, L.R.; Jiang, Mangieri, B.R.; and Arenkiel, Y.; N.J.; Xu, R.M.; Justice, Driven by a Defensive Behaviors Q. Tong, eNeuro, Midbrain Circuit. Hypothalamic-Ventral doi: pii: ENEURO.0156-19.2019. 2019 6(4). PMID: 10.1523/ENEURO.0156-19.2019. 31331938. L.R.; Zhu, R.M.; Mangieri, Cassidy, Y.; Lu, Y.; Xu, Y.; N.J.; Xu, Z.; Justice, X.; Jiang, Huang, Y.; Identification of a Q. Tong, B.R.; and Arenkiel, Neurociruit Underlying Regulation of Feeding by Nat Com- Stress-related Emotional Responses. doi: 10.1038/ 1;10(1):3446. Aug 2019 mun. PMID: 31371721. s41467-019-11399-z. LAB MEMBERS PhD MD, Xu, Yuanzhong Instructor: PhD Postdoctoral fellow: Zhiying Jiang, Canjun Zhu Graduate students: Ryan Cassidy, Hongli Li Jing Cai, Jessie Morrill, (visiting), (visiting) action on energy and glucose, and their action on energy and glucose, involvement in obesity and diabetes patho- genesis. metabolism. ing regulation and its relation with emotional ing regulation and its relation states. A) Diagram showing injections of GCaMP6 virus to both lateral hypothalamus (LH) and DBB (Diagonal Vgat-Cre mice and implantation of optic fibers to both LH and DBB for in vivo Band of Broca) of recording of neuron activity in both locations simultaneously. B) Simultaneous recording of LHVgat-GCaMP6m and DBBVgat-GCaMP6m population activity during showing opposite phase of neuron activities between the two groups of feeding bouts (shaded areas), neurons during feeding bouts due to GABAergic connections between them. •Chronic stress and obesity development. KEY PUBLICATIONS J.B.; Xu, Tian, M.; Jere, Y.; R.M.; Lu, Cassidy, B.; Selever, Felix-Okoroji, L.R.; Mangieri, Y.; A Q. lateral Arenkiel, B.R.; Tong, J.; Y.; Xu, hypothalamus to basal forebrain neurocircuit promotes feeding by suppressing responses Adv. Sci to anxiogenic environmental cues. doi: 10.1126/ 2019 Mar 6;5(3):eaav1640. PMID: eCollection 2019 Mar. sciadv.aav1640. 30854429. •Brain mechanisms mediating blood hormone Brain efferent pathways controlling peripheral •Brain efferent pathways controlling Brain control of feeding, body weight, and glucose metabolism and body weight, Brain control of feeding, RESEARCH PROJECTS for feed- •Novel neurons and neural pathways Qingchun Tong, PhD Tong, Qingchun Associate Professor in Molecular Medicine Cullen Chair The current obesity epidemic and its we employ various animal our goals, Toward One major direction in the lab is to identify associated metabolic syndrome have imposed unprecedented challenges to society and but with no apparent effective medicine, to Our research is directed therapeutics. understand the fundamental mechanistic insights on key driving causes for defective therefore feeding and body weight regulation, providing conceptual and effective targets for preventionand treatment of eating disorders, obesity and its associated diabetes. models in combination with the state-of-the- electrophysiology, including art techniques, and in vivo live chemogenetics, optogenetics, Cre-lox P mouse genetics is used imaging. to achieve manipulations in neuron-specific various adenoassociated viral Also the brain. vetors (AAV) harboring genes that exhibit Cre-dependent expression or inactivation will be stereotaxically delivered to specific brain achieving regions of Cre-expressing neurons, neuron-expression or inactivation of foreign tool Example foreign genes include specific genes. channels that either activate or inhibit neurons. virus-based tracing is used to map In addition, specific neural projections and their implica- are also We tions in physiology and behaviors. exploring CRISPR/Cas9 technology to achieve neuron-specific gene deletion in adult mice. These advanced techniques ensure our studies are effective and our conclusions are insightful. and map novel neurocircuits underlying emotion Emerging evidence suggests control of feeding. that feeding abnormalities are associated with defects in control of emotion and clinical drugs that reduce symptoms of psychiatric Using disorders cause obesity development. unique animal models coupled with behavioral we aim to delineate analysis and optogenetics, important neurons and neural pathways that underscore interactive regulation of feeding and This line of research is highly signifi- emotion. cant to current clinical treatments for obesity, and eating disorders. psychiatric patients, METABOLIC AND DEGENERATIVE DISEASES DEGENERATIVE AND FOR METABOLIC CENTER 38 • IMMPACT REPORT CENTER FORMETABOLIC AND DEGENERATIVE DISEASES tools inbothmodelorganism Drosophilaand of almostallbraindegenerative diseases. deposits areacommonpathologicalhallmark aggregates, tanglesandplaques, suchabnormal neuronalloss.eventual Commonlyknownas proteins andRNAsinthebrain, causing nonfunctional, leadingtodepositionoftoxic machineries oftenbecomeinefficientor neurodegenerative diseases, theseprotective recycle worn-outortoxiccellularmaterials. In protective machineriesthatcleanupand systems, whichare cellularclearanceand (meaning “self-eating” inGreek)andlysosomal in shape, aswell asproteasomes, autophagy include chaperonesthathelpproteinstostay and externalinsultsfordecadestocome. ies tostayhealthyandwardoffinternalcrisis neurons harborrobustself-clearancemachiner- replaced. To maintainlongevity, theselong-lived lose theirabilitytoreproduceandnolongerget interconnected functionalunits, mostly they arebornandmature into challenge: oncethey ished, unique neuronsfaceoneparticularly that areconstantlydividingandbeingreplen- some cells, suchasthosefromskinandblood connections insidethebody. However, unlike throughneuronsandtheir functional achieved diseases. these devastating from thesestudiesshouldhelpfindcuresfor operate properlyinaffectedbrains. Findings healthy duringnormalageingthatnolonger molecular machineries, insidecellstostay studies howneuronsnormallyutilizecertain becoming apressingthreattosociety. Ourlab financial tollstopatientsandtheirfamilies, inflictunbearablyhighemotional and but they andtherapeuticavenues,effective preventive incapacitating braindiseasesstilldonothave disease (PD), andothers. Bynow, these such as Alzheimer’s disease(AD), Parkinson’s aging-related neuronaldegenerativedisorders, tancy, wearealsobecomingmorevulnerableto Using genetic, biochemical, andcellbiology The self-maintenancemachinesinsidecells Our senses, reasoning, andresponsesare As weenjoyunprecedentedlongerlifeexpec- Becker FamilyFoundationProfessorinDiabetesResearch Associate Professor Sheng Zhang, PhD and schizophrenia. to aspectrumofdisordersincluding AD, PD, HD, neuronal functions. Their disruptionsarelinked and synapticvesiclescontrolmanyaspectsof autophagosomes, lysosome-relatedorganelles, diseases organelles andtheirdysfunctioninbrain autophagy. (HD), roleinselective playsanimportant for afataldegenerativeHuntington’s disease we foundthatHuntingtin, thegeneresponsible specificity foritsclearancetargets. Interestingly, autophagy disposalandrecycling.their eventual Selective unwanted orharmfulcellularcomponentsfor autophagosomes asgarbagebagstocollect protein deposits. capable ofdismantlinglargeandtightlypacked disaggregase, apotentmolecularmachine activities andisalsoamajorcomponentof theirnormal fold intopropershapestoachieve dant proteinsinthebrain. Ithelpsproteinsto neuronal survival particular, wefocusonthefollowingdirections: to fightagainstneurodegenerativediseases. In command theseinnateprotectionmachineries cellular constituents. Ourgoalistofindways away toxins, whilespareandprotectnormal the celltorecognizeandefficientlyclear self-maintenance machinesoperateinside mammalian systems, westudyhowthese Molecular mechanismsofneurodegenerativediseases present in cells expressing autophagy-inducer humanULK1gene.present incellsexpressing autophagy-inducer Numerous autophagosomes (redpunctainrightpanel), notfoundincontrolcells(leftpanel), are Induction ofautophagosomes inautophagy. Specialized cellularorganelles, suchas (2) Biogenesisofspecializedcellular During autophagy, cellsproduce Chaperone Hsp110isoneofthemostabun- pathwayson (1) Chaperonesandautophagy is a subtype of autophagy thatshows is asubtypeofautophagy •Mechanisms ofproteinfoldingandcellular RESEARCH PROJECTS •Endogenous functionsofHuntingtinandits •Biogenesis ofautophagosomesandlysosome- Research assistants:Xin Ye, PhD;Mrs. Lili Ye (rotating GSBSstudent) Students: Yue Yu,Graduate Solbach Amanda Post-doctoral fellow:GangLi, PhD ShiyuXu,Instructor: PhD LAB MEMBERS 15(7):1214-1233. Autophagy for autophagicandlysosomaldegradation”. Bellen, H.J. (2019): “Vap proteinsarerequired B.; Zhang, S.; Arenkiel, B.R.;Sardiello, M.;and Mao, D.X.; Lin, G.;Senturk, M.;Zuo, Z.Y.; Tepe, pathological Tau”. andspreadingthroughselectivetargetingof ogy cargo receptorSQSTM1ameliorates Tau pathol- Xu, Y.; Zhang, S.;andZheng, H. (2019): “The 51. (*correspondingauthors) Pontin/Reptin Complexes.” DevCell. 36(2):139- Activity by Acting asan Adaptor forthe TTT and S.;* Bellen, H.J.*(2016) “WAC Regulates mTOR Zhang, K.;Sandoval, H.;Duraine, L.;Zhang, W.L.; Jaiswal, M.; Yamamoto, S.;Xiong, B.; David-Morrison, G.;Xu, Z.;Rui, Y.N.; Charng, KEY PUBLICATIONS disorders. clearance pathwaysinbraindegenerative perturbation inHuntington’sperturbation disease. related organelles. Autophagy 15(4):583-598. Autophagy IMMPACT REPORT • • • • 39 In addition to having an assembly of faculty- addition In photonics technologies for better diagnosis and photonics technologies for better diagnosis Conditions such as vascular treatments. directed anomalies, congenital heart peripheral disease, and head and cancer, disease, breast vascular our using under investigation neck cancer are imaging technologies. Earlier, investigational visualization translational activities further explore preclinical of brain function in neonates, and in into the models of human disease, CSF outflow detection of lymph lymphatics, and intraoperative team Our node metastases and tumor margins. focuses upon translating new NIRF molecular that standards imaging agents using validated photonics device difference can be applied across platforms. independent basic science and clinical driven the center synergistically projects, research clinicians center where operates a “collaboration” partner apply to effectively and researchers and translate imaging diagnostics to investigate therapeutics. novel PhD Sevick-Muraca, Eva & Professor Director Center and Rich Kinder Distinguished Chair in Nancy Disease Research Cardiovascular for in the NCI Network Center Director, Research Translational

he Mission of the Center for Molecular of the Center for Molecular he Mission and translate (CMI) is to develop Imaging new medical imaging technologies,

The CMI houses a diverse, interdisciplinary The CMI houses a diverse, A highlight of the CMI is the basic science/ MOLECULAR IMAGING FOR MOLECULAR CENTER

molecular imaging agents, and companion molecular imaging agents, and companion diagnostics to accelerate discoveries. and develop team of scientists and engineers who and use multi-modality molecular diagnostics imaging, imaging techniques, including nuclear bioluminescence, X-ray computed tomography, fluorescence and near-infrared fluorescence, (NIRF) to enable new understandings of conditions. Sponsored disease and chronic and federal research philanthropic, industry, funding focuses upon autoimmune disorders, cancer metastases, hemo- and neuroinflammation, diseases, and lymphedema. The lymph-vascular team has experts in instrumentation, imaging antibody engineering, animal agent development, models of human disease, and translational and inventions moves science that effectively and when “bench to bedside,” discoveries, “bedside made in the clinic, from are discoveries back to bench.” clinical translational team that engages clinicians and at partnering institutions on at UTHealth Center and in the Houston Medical Texas the clinical studies suburbs. These FDA-approved enable visualization of the lymphatic system using T 40 • IMMPACT REPORT CENTER FORMOLECULARIMAGING near-infrared fluorescence imagingofthe Ab aggregationandplaqueformation. disease, isimpairedandpresumablyleadsto watershed, andinanimalmodelsof Alzheimer’s in thebraindrainsintocervicallymphatic brain, thecerebrospinalfluid(CSF)generated disease andprecedeulcerformation. Inthe insufficiencies accompanyperipheralvascular populations, wehave foundthatlymphatic example, inthelower extremitiesofaging products andunresolvedinflammation. For insufficiency canresultinthebuild-upofwaste the hemovascularcirculatorysystem. Lymphatic waste productsandexcessfluidforreturnto immunosurveillance butalsotocollectcellular one lymphaticwatershednotonlytoensure immune responsesthatbreakcentraltolerance. results and, perhapsnotsurprisingly, adverse tical strategiesfrequentlyleadtosuboptimal as inautoimmunetherapies, thesepharmaceu- or toattenuateimmuneresponsesagainstself cancer checkpointblockadeimmunotherapies, dosed tostimulatetheimmunesystemasin are administeredordosedsystemically. Whether signalingmoleculeswithinthe lymphatics key tended toalterimmuneresponsesbytargeting organization oflymphatics, drugsthatarein- or tolerancetoself. Yet despitethewatershed immune systemandbreakingcentraltolerance, multiple antigenswithoutoverwhelmingthe regional processingofimmuneresponsesto blood vasculature. This organizationenables node anddisseminatethroughthebodyvia activate immunecellsthatthenleavethelymph draining lymphnodes, antigensarepresentedto hemovascular circulatorysystem. Intheregional lymph nodebasinsbeforeemptyingintothe is organizedintowatershedsthatdrain nodes. The decentralizedlymphatic system one dependentuponregionaldraininglymph fromacentralizedlymphatic systemto evolved increased andtheadaptiveimmunesystem into landdwellers, terrestrialantigenexposure In ourresearchprogram, weemploy In addition, alltissues draintoatleast fromthesea evolved As highervertebrates Nancy andRichKinderDistinguishedChairinCardiovascularDiseaseResearch Professor andDirectoroftheCenterforMolecularImaging Eva MarieSevick-Muraca, PhD immune relatedadverseevents. Adapted fromKwon, Setal., Theranostics , 2019. However, innon-TDLN, anti-CTAL-4 takesthebrakesof T cellactivationagainstselfantigensleadingto (TDLNs). There anti-CTLA-4takesthe “brakes” of T cellactivationagainsttumorantigen(greenballon). Site ofactionforcheckpointblockadeimmunotherapyisintheregionaltumordraining lymphnodes •Refining measurementsoflymphaticanatomy •Assessing theroleoflymphaticsinmetabolic •Evaluating theroleofCSFoutflowinbrain •Lymphatic deliveryofimmunotherapiesfor RESEARCH PROJECTS of chronicconditions. lymphatic imagingtoprovidebetterdiagnostics conditions. methodsof We alsoengineernew andtreatmentofthese to betterprevention biologicalinsightsthatcouldlead new develop these conditions. Ourstudiesaredesignedto investigate thecorrespondinganimalmodelsof Medical Centerwithchronicconditionsand of infants, children, andadultsonthe Texas Specifically, weconducttranslationalimaging therapeutics thatcanmodulateimmunity. the lymphaticsandtomoreeffectivelydeliver to understandchronicconditionsthatinvolve lymphatic vasculatureanditsfunctioninorder health andchronicdisease Understanding howthelymphaticwatershedsmediateimmune and function. disorders. and Alzheimer’s. health cancer andautoimmunedisorders. 9(26):8332-8343, 2019. improved anti-tumorresponses,” Theranostics, of checkpointblockadeimmunotherapyfor “Nanotopography-directed lymphaticdelivery W.J.; Ross, R.F.; andE.M. Sevick-Muraca, Greives, M.R.; Turner, K.;Morrow, J.R.;Hwu, Kwon, S.; Velasquez, F.C.; Rasmussen, J.C.; ease, 69(2):585-593, 2019PMID31104026. model ofalzheimer’s disease,”Dis- JAlzheimer’s and cerebrospinalfluidoutflowinamouse E.M., “Impaired peripherallymphatic function Velasquez, F.C.; Soto, C.;andSevick-Muraca, Edwards IIIG.;Gamez, N.;Calderon, O.; Zhu, B.; Kwon, S.;Morena-Gonzalez, I.; Taylor-Presse, K.; ment, 19(1):116, 2017PMID:28566090. induced arthritis,”Research AndTreat Arthritis - nanotopography improvesresponsetocollagen- Muraca, “Lymphatic deliveryofetanerceptvia W.; Rasmussen, J.C.;Ross, R.F.; andE.M. Sevick- Azhdarinia, A.; Pinkston, K.;Harvey, B.R.;Chan, Aldrich, M.A.; Velasquez, F.C.; Kwon, S.; KEY PUBLICATIONS IMMPACT REPORT • • • • 41 lymphedema. lymphovenous anomalies. RESEARCH PROJECTS cancer-related •Longitudinal study of breast •Imaging of lymphatics in lipedema. and pediatric •Imaging of neonatal chylothorax KEY PUBLICATIONS New and emerg- M.B. Aldrich, M.V.; Schaverien, Semin Plast ing treatments for lymphedema. 2018. 32:48-52, Surg S.; Kwon, F.C.; Velasquez, M.B.; Aldrich, W.; B.; Chan, K.; Harvey, A.; Pinkston, Azhdarinia, C.E.; Sevick- Fife, R.F.; J.C.; Ross, Rasmussen, Lymphatic delivery of etanercept E.M. Muraca, via nanotopography improves response to Arthritis collagen-induced arthritis. Res Ther 2017. 19:116, C.E.; J.R.; Fife, Morrow, D.; M.B.; Gross, Aldrich, Effect of pneumatic compres- J.C. Rasmussen, sion therapy on lymph movement in lymph- by as assessed edema-affected extremities, near-infrared fluorescence lymphatic imaging. J 02, No. 10, Vol. Innov Optical Health Sciences, 1650049 doi: 10.1142/S1793545816500498, March 2017. LAB MEMBERS Medical student: Kay Pham NIRFLI studies of patients with lipedema, NIRFLI studies of patients with lipedema, Chylothorax occasionally affects neonatal Near-infrared fluorescence lymphatic imaging (NIRFLI) of arm lymphatics in a patient with breast Near-infrared fluorescence lymphatic imaging (NIRFLI) of arm lymphatics in a patient with pumping through Green fluorescent dye is visualized through the skin, cancer-related lymphedema. Medical insurers need objective vessels (in a healthy arm) or pooling as backflow (in lymphedema). These images are evidence actually works. that currently prescribed physical therapy for lymphedema the first visual proof of reversal of lymphedema in response to therapy. Imaging in immunologyImaging In a rat and minimize off-target toxicities. NIRFLI revealed model of rheumatoid arthritis, factor-alpha that delivery of a tumor necrosis through lymphatic (TNF-alpha) blocker directly in significantly vessels to lymph nodes resulted as evidenced by reduced disease activity, improved lymphatic pumping. a fat disorder that affects ~11% of women, revealed leg lymphatic vessels are dilated that suggesting the disease is an and slow-pumping, Compression garment inflammatory disorder. wear to promote leg lymph movement and anti- inflammatory dietary practices have improved member of I am a outcomes for these patients. the Center for Molecular Imaging (CMI) team that participatesof with a national coalition researchers to investigate lipedema. heartI here surgery patients.My colleagues and at CMI and Memorial Hermann Hospital have used NIRFLI to help visualize the source of pleu- also We ral effusion in babies with chylothorax. have imaged numerous pediatric patients with lymphovenous anomalies to help physicians direct optimal care. Melissa B. Aldrich, MBA, PhD MBA, Aldrich, Melissa B. Assistant Professor Cancer survivors face the possibility of Delivery of pharmacological therapeutics developinga devastating side effect of cancer as a which manifests treatment: lymphedema, or trunk. neck, leg, permanently swollen arm, Lymphedema requires constant compres- and meticulous skin care, sion garment wear, patients Lymphedema specialized massage. cellulitis bouts, depression, suffer discomfort, and there is no cure—only palliative treatment. in if caught early Studies have shown that, lymphedema treatment can development, Near-infrared fluorescence reverse disease. the lymphatic imaging (NIRFLI) imaging delivers low-cost images of lymphatic high-resolution, In disease vessel architecture and pumping. imaging NIRFLI states such as lymphedema, can provide information for early diagnosis and I lead a five- evaluationof treatment efficacy. year prospective and longitudinal study using NIRFLI surveillance of breast cancer patients to identify early lymphedema development and biomarkers that could suggest pharmacologi- I recently presented evidence cal treatment. at an international conference showing that I also lymphedema is reversible at early stages. participate as a team member imaging treat- ment responses to head and neck lymphedema, which affects ~90% of head and neck cancer pneumatic The treatment used, patients. removes stagnant lymph compression therapy, but needs NIRFLI to in lymphedema patients, to medical insurers that the “prove” visually I am very active in the therapy actually works. and I was recently ap- lymphedema community, Advisory pointed to the Scientific and Medical Council of the Lymphatic Education & Research an international organization Network (LE&RN), and pa- therapists, physicians, of researchers, dedicated to advancing lymphatic health. tients, I also chaired the committee that established Centers of Excellence standards for LE&RN’s which will enable patients to locate designation, institutions with lymphatic expertise. directly to the site of disease activity could reduce the amount of pharmaceutic required, MOLECULAR IMAGING FOR MOLECULAR CENTER 42 • IMMPACT REPORT CENTER FORMOLECULARIMAGING predicting onset, progression, andresponseto and neckcanbeused asadiagnostictargetfor peripheral lymphatics outflowfromthehead School. This isthefirsttimetoshowthat for Alzheimer’s diseaseatMcGovernMedical Ines Moreno-GonzalezintheMitchellCenter in collaborationwithDrs. ClaudiaSotoand of amyloidbeta(Aβ)plaqueaccumulation may impactglymphaticfunctionatearlyonset of Alzheimer’s disease(AD)isimpairedand lymphatic systemoftransgenicmousemodels area. Recently, Ishowedthattheperipheral lymphatic vasculaturewithintheheadandneck that ultimatelydrainintotheperipheral (ISF) areexchangedthrough “glymphatics” spinal fluid(CSF)andbraininterstitial the untreatedcohort. tumor shrinkageoccurredwhencomparedto successfully deliveredviathelymphaticsystem, lymphocyte–associated antigen4(CTLA-4)was that whentherepeateddoseofanti-cytotoxic T- systemic anti-tumorimmunity. Idemonstrated stimulation totheregionallymphaticsfor and toreducetoxicitybylocalizingimmune drug exposuretotumor-draininglymphnodes forimmunotherapy tomaximize infusion device rat model. Recently, Iusedthenovellymphatic tional routesofadministrationinanarthritis systemic responseswhencomparedtoconven- the lymphaticscanresultinimprovedlocaland infusion ofanimmune-attenuatingbiologicinto metastasis, hypertension, andinflammation. age patternsinanimalmodelsoflymphnode showed abnormallymphaticfunctionanddrain- and disease. Usingthisnoveltechnique, we ing andquantifyinglymphaticfunctioninhealth fluorescence (NIRF)imagingmethodsforimag- non-invasive,developed dynamicnear-infrared ticularly inthelymphaticsystem. Recently, we movement offluidandmacromolecules, par- focuses oninvestigatingthemicrocirculatory biological questions. Mymainresearchinterest small animalimagingtechniquestoaddress Recent evidence demonstratesthatcerebral Recent evidence Recently, CMIdemonstratedthatdirect andapplicationof I leadthedevelopment Sc, Scapula. brachial LN. RA/LA, right/left axillaryLN. RI/LI, right/leftinguinal LN. T, tumor. M, muscle. S, stratum. 15, 19, and23dayspostimplantation. H, heart. RS/LS, right/leftsubmandibularLN, RB/LB, right/left Carolyn FrostKeenanProfessorinCardiovascularDiseaseResearch Assistant Professor Sun KukKwon, PhD CTLA-4 administeredi.p., (blue)orwithSOFUSA A. 4T1-LucinBalb/cmicetreatedwithcontrolantibody(black)or Growthratesoforthotopic •Using non-invasivelymphaticimagingtoshow •Assessing thenormallymphaticdrainagein forquan- PET/CTmethodology •Developing •Characterizing impairedcerebrospinalfluid •Non-invasive dynamiclymphaticimagingto RESEARCH PROJECTS myocardial infarctinmice. lymph nodemetastasis, inflammation, and conducting molecularimagingofcancerand and translatingimagingagents. Iamcurrently The CenterforMolecularImagingisdeveloping volve aroundmulti-modalitymolecularimaging. AD pharmacologicalintervention. Lymphatic functioninhealthanddisease after tumorinoculationandtissues euthanasia. CTLA-4wastreatedi.p orviaSOFUSA were made. B. 4T1-LucinBalb/cmice16, Bioluminescenceimagingoforthotopic 23, and30 days ment days. The meantumorvolumes±SE(bars)areshownatthetimesthat tumormeasurements of whichmimicsaspectsmicrogravity. position andheaddowntilt(HDT), thelatter istration ofICG, underconditionsofsupine region afterintradermalandintraoraladmin- the lowerextremitiesaswellincervical with Dr. JungSuhatRiceUniversity. myocardial infarctinmicecollaboration tifying infarctsizeingenetherapytrialsof medical school. collaboration withDr. ClaudioSotoatthe in Alzheimer diseaseanimalmodelsin (CSF) drainageintoperipherallymphnodes phatic vesselintegrityaftercancertherapy. of melanomaandrestorationnormallym- show lymphaticremodelinginamousemodel Other directionsofmyscientificinterestsre- TM deliveredCTLA-4(red). arrowsindicatetreat- Grey Pinal (summerpre-Baccalaureatestudent) C.J.assistants: Vaelasquez,Research Amanda LAB MEMBERS 9; 4631-4637. 2018. murine melanoma,” BiomedicalOpticsExpress, endothelial growthfactor-Coverexpressing fluorescence lymphaticimaginginvascular and EvaM. Sevick-Muraca, “Near-infrared Sunkuk Kwon, FredChristian, Velasquez, logical Methods, 449;37-43. 2017. cerebrospinal fluidinmice,” Journal ofImmuno- “Fluorescence imagingoflymphaticoutflow Christian, Velasquez, andEvaM. Sevick-Muraca, Sunkuk Kwon, ChristopherF. Janssen, Fred 7 pages, 2017. lecular Imaging, vol. 2017, ID7659242,Article Fluorescence Imaging,” Contrast Media&Mo- tion andDiet-InducedFluorescenceonInVivo “Effects ofDepilation-InducedSkinPigmenta- Sunkuk KwonandEvaM. Sevick-Muraca, KEY PUBLICATIONS efficacy ofdrugdeliverywithSOFUSA Clark Coop(CurrentlySorrento Therapeutics). byKimberly translated tohumanssupported the lymphnodesinmiceandsuccessfully TM at11, TM into IMMPACT REPORT • • • • 43 development arte of peripheral venous and - rial disease. to intervention. lymphedema and its response pediatric population. RESEARCH PROJECTS in the •Understanding the role of lymphatics •Assessing the development of cancer-related of lymphatic imaging to the •Translation KEY PUBLICATIONS M.B.; Aldrich, S.; R.J.; Naqvi, C.; Karni, Gutierrez, E.M.; and J.R.; Sevick-Muraca, B.; Morrow, Zhu, “Head and neck lymphedema: J.C., Rasmussen, treatment response to single- and multiple sessions of advanced pneumatic compres- and Neck Otolaryngology-Head sion therapy,” 2019. 160(4):622-626, , Surgery M.; J.C.; Litorja, S.; Rasmussen, B.; Kwon, Zhu, “Comparison of NIR E.M., and Sevick-Muraca, versus SWIR fluorescence image device perfor- mance using working standards calibrated with on Medical Imaging , Transactions IEEE SI units,” epub 8/27/2019. J.C.; Rasmussen, F.C.; Velasquez, S.; Kwon, J.R.; Hwu, K.; Morrow, Turner, M.R.; Greives, Sevick-Muraca, and E.M. R.F.; W.J.; Ross, “Nanotopography-directed lymphatic delivery of checkpoint blockade immunotherapy for Theranostics, improved anti-tumor responses,” 2019. 9(26):8332-8343, We are also using NIRF imaging to assess the are also using NIRF imaging to assess We continue the developmentWe of this technol- Normal lymphatic vessels in a healthy volunteer (left, adapted from Rasmussen, et al., J. of Vas. Surg.: Vas. of J. et al., adapted from Rasmussen, Normal lymphatic vessels in a healthy volunteer (left, 2016) and abnormal lymphatics in a patient with (center) C3 venous 4(1), Dis., and Lymph. Ven. disease with segmented lymphatics and (right) C4 venous disease with indistinct lymphatic vessels. Deviceimaging for lymphatic translation cious therapeutic approaches. of the lymphatics after or lack thereof, recovery, are particularly We interested cancer treatment. population as it in the head and neck cancer has been reported that 75% of head and neck cancer survivors will develop lymphedema. Our imaging has shown the development of with abnormal lymphatics in this population, the extent of abnormal lymphatics generally increasing with time (months) after the end used NIRF recently We of radiation treatment. imaging to assess the lymphatic response to a advanced pneumatic compression device new, developedspecifically for subjects with head and neck lymphedema and reported- a reduc tion in the extent of abnormal lymphatics with as little as two weeks of intervention in 75% of to assess Ongoing studies also seek subjects. treatment efficacies of improved pneumatic compression devices in subjects with breast as the as well cancer-related lymphedema, relationship between the lymphatics and other including lipedema. disorders, including assessing novel imaging and ogy, device improving drug delivery technologies, different aspects of automating sensitivity, and developing analytical tools the hardware, to facilitate lymphatic image processing and analysis with the ultimate goal of answering new biological and clinical questions not addressed by other technologies. John Rasmussen, PhD John Rasmussen, Assistant Professor The lymphatic system is a vital, yet poorly yet poorly The lymphatic system is a vital, One of our primary focuses is the relation- component of the circulatory understood, blood flows through the arteriesAs and system. entering water leaks from the vessels veins, As the the small gaps between the tissue cells. water moves through the tissues it picks up etc., proteins, foreign contaminants, cell waste, and the resulting solution is taken up by the processed for immune response, lymphatics, In addi- and is ultimately returned to the veins. for the the lymphatics provide a pathway tion, However, absorption of nutrients from the gut. because the lymphatics are typically small and they are difficult primarily transport clear fluids, to distinguish from the surrounding tissues, either with our eyes or using traditional clinical X-ray, imaging modalities such as scintigraphy, Over the past few years, and ultrasound. MRI, my research has focused upon the development and translation of near-infrared fluorescence (NIRF) optical imaging as a way to noninvasively image and characterize human lymphatics and quantify their contractile function in health and disease using microdose amounts of a fluorescent contrast agent. ship between the lymphatics and the blood It has been known for many circulatory system. years that patients with advanced chronic venous disease often co-develop lymphedema, a condition of chronic swelling with fibrotic We tissue changes and poor immune response. recently imaged a group of patients with active venous leg ulcers and demonstrated abnormal lymphatics in all the legs with advanced what was most surprising was However, disease. that we also observed lymphatic abnormalities including those with in all the contralateral legs, In following no external sign of venous disease. studies of subjects with early venous disease, we have observed a degradation of lymphatic anatomy and decreased lymphatic pumping, which corresponds with increased classification A better understanding of the of venous disease. role of the lymphatics in early vascular disease may enable the development of more effica- MOLECULAR IMAGING FOR MOLECULAR CENTER 44 • IMMPACT REPORT Currently, anICGbasedfluo- wearedeveloping willbecomelimited.SWIR imagingdevices advancesinbothNIRFand of rapidlyevolving using atraceableinvitrotest, clinicaladoption quantitative comparison. quantification Without tify performanceoftheseimagingsystems limits thelackofworkingstandardstoquan- however ing camerashavebeenqualitativelycompared, commercial Si-basedandInGaAs-basedimag - Images ofICGinsmallanimalsacquiredby also hasfluorescenceemissioninSWIRregime. (ICG), usedclinically asaNIRFcontrastagent, tion, andthediscovery thatindocyaninegreen autofluorescence, comparable tissueabsorp- to thereducedtissuescattering, negligible near-infrared fluorescence(NIRF)imagingdue posed ashavingadvantageoverconventional light (SWIR, 1,000-2,000 nm)hasbeenpro- infrared fluorescence imagingusingshortwave standards calibrated withSIunits:Recently, image deviceperformanceusingworking the averagedBOLDfMRIvolume. static CTOT volumesarestronglycorrelatedwith inanawakechildandthe the cerebralcortex to obtainahigh-resolutionfunctionalmapof amount ofhigh-qualityCTOT data, weare able brain hemodynamicactivity. anincreased With Optical Tomography (CTOT) toimagewhole paradigm, calledCap-based Transcranial novel transcranialnearinfraredopticalimaging surface.cortical Currently, a wearedeveloping thatrestrictmeasurements tothe field-of-view detector pairs, detectorsensitivityaswellthe systems arelimitedinthenumberofsource- current versionsofcontinuouswavefNIRS-DOT alternative brainnetworkimagingtechnique. Yet (fNIRS-DOT) imagingpromisestobean Spectroscopy –DiffuseOptical Tomography and smallchildren. FunctionalNear-Infrared anesthesia limitsitspracticalutilityininfants brain functioninadults, theneedforgeneral functional MRI(fMRI)iswidelyusedtoexamine Dependent(BOLD) Blood OxygenationLevel for wholebrain functionalmapping:Although CENTER FORMOLECULARIMAGING Comparison ofNIRversusSWIRfluorescence Cap-based TranscranialOptical Tomography Assistant Professor Banghe Zhu, PhD right isanterior. and theventriclesmaskedpriortocrosscorrelation. Forallimagesthetopofimage issuperior, and image (CTOT-nHbT). NIHheatmapwasused(seerightcolorbar). All imageshadnon-brainstructures ized intensityCTOT-HbR image(CTOT-nHbR), and(d)SagittalsliceofthenormalizedintensityCTOT-HbT Sagittal sliceofthenormalizedintensityCTOT-HbO image(CTOT-nHbO), (c)Sagittalsliceofthenormal- (a) Sagittalsliceoftheoneminusnormalized intensityprocessedBOLDimage(1-nBOLD), (b) calibrated withSIunits performanceusingworkingstandards rescence imagedevice functional mappingandcomparisonofNIRversusSWIRfluo- Cap-based transcranialopticaltomographyforwholebrain image performance,” IEEE Transactions on- Medi indocyanine greenusingSI-derivedmetricsof of NIRversusSWIRfluorescenceimaging M.; andSevick-Muraca, E. M., “Comparison Zhu, B.;Kwon, S.;Rasmussen, J. C.;Litorja, KEY PUBLICATIONS • • • • RESEARCH PROJECTS tion inlargeanimals. as wellwaterabsorptionlimitsdeeppenetra- lack ofmeasurementsensitivity, SNR, contrast, animal imagingcomparedtoNIRFimaging, but of ICGmayhavesuperiorresolutioninsmall results suggestthatSWIRfluorescenceimaging fluorescence andNIRFimagingsystems. Our for qualitativecomparisonofthesameSWIR small animalandlargeimagingwithICG non-clinical tests. Inaddition, weareperforming signal-to-noise ratio(SNR), andcontrastin Si, andInGaAsbasedcamerasystems, their measurement sensitivityofSi, GaAs-intensified SI units(mW·cm-2·sr-1)forquantificationof rescent solidworkingstandardcalibratedwith Perform head&necksurgeryclinicalstudies. studies. Perform peripheralvasculardiseaseclinical mance comparison. perfor- workingstandardsfordevice Develop CTOTDevelop imagingsystem. Express. 5(2):562-572(2014). ICCD andlaserdiode,” BiomedicalOptics ambient lightconditionsusingamodulated M., “Non-invasive fluorescenceimaging under Zhu, B.;Rasmussen, J.C.;andSevick-Muraca, E. 3351 (2015). discovery”, BiomedicalOpticsExpress, 6:3346- preclinical models:atoolforacceleratingdrug imagingofcancermetastasisin gene-reporter Sevick-Muraca, E. M., “Longitudinal farred Zhu, B.;Robinson, H.;Zhang, S.; Wu, G.; and tion”. J. Cell. Biochem. 9999:1–8, 2017. Approach toSelectively Turn offBoneForma- E., ofaCell-basedGene “Development Therapy G.; West, J.;Sevick, E. M.;Davis, A.; OlmstedD. Alvarez-Urena, P.; Zhu, B.;Sonnet, C.;Henslee, Molecular Therapy, 27, 611-622, (2019). tissue,”for genedeliverytodamagedheart activatable adeno-associatedvirusvector Agbandje-McKenna, M.;andSuh, J., “Protease- S.; Evans, A. C.; Voss, J.;Sevick-Muraca, E. M.; Chen, W.; Zhu, B.;Lam, M.; Yamagami, M.;Kwon, Guenther, C. M.;Brun, M.;Bennett, A.; Ho, M. L.; (2019). DOI:10.1109/TMI.2019.2937760 cal Imaging, IMMPACT REPORT • • • • 45 Our center houses several core facilities, core center houses several Our for large cohort study. We also have an active an active also have We for large cohort study. that includes program development probe of new aptamers and multi- the development functional nanoparticle therapeutics for targeting addition, In pathological tissues, such as cancer. expertise and have in the development we biologics, namely antibody- application of novel imaging and therapeutic based agents that have as infectious implications in cancer as well in the center specializes diseases. Furthermore, of multifunctional peptides that the development contrast to and fluorescent combine radioactive during, and enable tumor identification before, surgery a precision thus introducing after surgery, large-scale, multi-color, also have We approach. state-of-the-art 3D printers for high-resolution level and finished production both fast prototypes models of new surgical tools and instruments or patient-specific organ models. Service Center, including the Nanochemistry 3D-printing Service Center and Clinical, and to Service Center, Proteomics Translational service labs through support and many research efforts.collaborative ScD PhD, MA, MB, BChir, Hancock, John Medicine of Molecular Institute Director, Executive Chair in University S. Dunn Distinguished John Physiology and Medicine

recision recision aims medicine to personalize

The current The current These efforts connect us with collaborators, patient care with patient care medical tailored decisions, treatments, relies and practices. It on the context of a genome, patient’s health proteome, demographics, history, or and other molecular cellular information. Thus, technologies, such as “omics” molecular approaches, diagnostics, imaging, and targeted delivery, bioinformatics, are implicated to facilitate medicine. precision in the Center research several emphasizes Biomedicine for Precision including application of analytical and areas, molecular translational technologies to investigate underlying malignancy and other diseases, events targeting of molecules for selective development of targeted development of tissues or toxins, and contrast agents for disease visualization, alterations to elucidate disease study of proteome to facilitate biomarkers mechanism and discover as well early detection and therapeutic treatment, imaging in proteomics, as technology innovation agents, and nanomedicine. such as physicians, pathologists, biologists, bioinformaticians, and bioengineers, across Medical Texas institutions within the UTHealth, to enhance basic, Texas and across Center, the IMM, At translational, and clinical research. state-of-the-art have mass spectrometers, we analysis of cells, in-depth proteomic providing tissues, or biological fluids, with the goals to to inform targets and biomarkers novel discover of therapeutic treatment the development and early detection of diseases. These studies, with the aid of bioinformatics and systems characterization of protein span from biology, and post-translational modifications to profiles alterations, as network of protein interrogation biomarkers as targeted analysis of protein well disease and other diseases neurological in cancer,

PRECISION BIOMEDICINE FOR PRECISION CENTER P 46 • IMMPACT REPORT 1864, 2017. PMID:28572490. Receptor Targeting. Retains forSomatostatin Agonistic Properties A.* A ModularDualLabelingScaffold That Schonbrunn,N.L.; A.;Azhdarinia,J.; Wilganowski, Ghosh, S.C.;Rodriguez, M.;Carmon, K.S.; Voss, (* denotescorrespondingauthor) KEY PUBLICATIONS •Receptor-targeted deliveryofchemotherapy ofcontrastagentsforreal-time •Development RESEARCH PROJECTS improve humanhealth. discoveries andtechnologiesintotheclinicto to eachprojectisourfocusontranslationof antibody-based cancertreatments. Common and assessingtheeffectivenessofemerging of novelnanomaterialsforbiomedicaluse, imaging of “good” fattissue, characterization cancersuch as collaborations inareasbeyond acterization hasallowedustoestablishdiverse inchemistry,expertise imaging, anddrugchar- ment protocols. Importantly, ourfundamental and visualizetheeffectstopersonalizetreat- platform tospecificallydelivertoxinstumors is notpossible, weaimtouseourchemistry In caseswherecancerhasspreadandsurgery would otherwisebemissedbythenakedeye. healthy tissues, andidentifysmalltumors, which cancer fromnormaltissue, minimizeremovalof intraoperative imagesthatwilldistinguish potentially providesurgeonswithreal-time intraoperative imaging, respectively. This could specifically identifycancerbywhole-bodyand approachesto new has allowedustodevelop fluorescent labelsontotumor-seekingagents For example, theadditionofradioactiveand multiple labelsandthus, multipleapplications. we havetheabilitytoproducemoleculeswith of disease. Usingnovelchemistryplatforms, molecules forthevisualizationandtreatment andisfocusedondeveloping and biology CENTER FORPRECISIONBIOMEDICINE agents fortreatmentofcancer. surgical guidance. My laboratoryisattheinterfaceofchemistry J. NuclMed.58(11):1858- Associate Professor Ali Azhdarinia, MS, PhD confirmed invivofindings. uptake intumorsthatexpresssomatostatin receptors(arrowsindicatetumor). (B)Exvivoimaging infrared fluorescenceimaginginmicewith (HCT116-SSTR2)andwithout(HCT116-WT)showedspecific In vivoandeximagingwiththemultimodalitycontrastagent, MMC(IR800)-TOC. (A)Invivonear- multimodality imaging. Chemical structureofahybridsomaostatinanalogcontainingradiaoctiveandfluorescnetlabelsfor Fisher,Dhingra,S.; W.E.;Azhdarinia,Specific A.* Ghosh, S.C.; Tran Cao, H.S.;Simien, J.;Reiner, T.; Hernandez Vargas, S.;Kossatz, S.; Voss, J.; 2019. PMID:30733318. Imaging Agents.lar inDual-labeledMolecu- Developments A.* New Hernandez Vargas, S.;Ghosh, S.C.; Azhdarinia, Molecular imagingprobedevelopment John S. DunnResearchScholarIII J NuclMed.60(4):459-465, Research scientist:SukhenGhosh Graduate students:ServandoHernandez Vargas Postdoctoral fellows:Solmaz AghaAmiri LAB MEMBERS 25(14):4332-4342, 2019. PMID:31015345. fluorescence-guided surgery. ClinCancerRes. targeting ofsomatostatinreceptorsubtype-2for IMMPACT REPORT • • • • 47 * Co-Corresponding Authors Tisza, M.J.; Sjol, J.S.; Chen, X.; Levental, I.;* and Levental, X.; J.S.; Chen, M.J.; Sjol, Tisza, Motility and stem cell proper- J.T.:* Chang, ties induced by the Epithelial-Mesenchymal of lipid rafts. require destabilization Transition 2016. Oncotarget, bioinformatics Planning J.T.: Chang, and X. Chen, Bioinformat- workflows using an expert system. 2017. ics 33(8), LAB MEMBERS PhD Zhao, Weina Instructor: PhD Research scientist: Xuan Liu, MB Research assistant: Jiayi Liu, formatic analysis. cancers. stem cell differentiation, the epithelial- stem cell differentiation, and cancer to-mesenchymal transition, metastasis. KEY PUBLICATIONS KEY PUBLICATIONS L.; M.J.; Li, Tisza, B.; S.; Urban, W.; Prijic, Zhao, J.T.: S.A.; and Chang, X.; Mani, Z.; Chen, Tan, Candidate anti-metastasis drugs suppress the metastatic capacity of breast cancer cells by Cancer Research reducing membrane fluidity. 2016. 76(7):2037-49, genomics to profile metastatic tumors to determine patterns of dissemination and are using We This shows the diversity of genetic phenotypic changes that occur in cells as metastases develop. While the genotypes subclones from a patient with metastatic disease originating from the left breast. they diverge as the disease spreads outward. of the breast tumors are relatively homogeneous, •Intelligent computational pipelines for bioin- Heterogeneity and progression of metastatic •Heterogeneity and progression Deciphering the signaling programs underlying cancer Deciphering the signaling metastasis RESEARCH PROJECTS in cancer •The role of cholesterol trafficking Jeffrey Chang, PhD Jeffrey Chang, Associate Professor in Cancer Research CPRIT Scholar Our lab is focused on understanding the Our research program encompasses two It is estimated Breast cancer metastasis. 1. Artificial intelligence for genomic analysis. 2. signaling programs underlying cancer progres- sion and developing therapeutic strategies wish to We to prevent treat metastasis. or understand the events that lead tumor cells to acquired whether through become metastatic, Our mutations or epigenetic mechanisms. ultimate goal is to translate these findings into the clinic through the development of genomic do To biomarkers and repositioning of drugs. encompass- we use a range of approaches this, and biochemistry; cell biology, ing genomics, mouse and use models including cell culture, and clinical samples. models, broad and complementary areas of emphasis: that up to 90% of cancer deaths are due to in part metastatic cells do because metastasis, address To not respond to traditional therapies. we have used computational this problem, approaches to reposition drugs to target cells that exhibit phenotypes that promote metas- we have found that Through this study, tasis. metastasis is driven in part by cells that acquire a stem-like state through deregulation of cho- lesterol metabolism through altered expression We are ABCA1 cholesterol efflux channel. of the currently identifying therapeutic strategies to inhibit this pathway to reprogram breast cancer stem cells so that they become more amenable to therapies. Many of our projects requires the integration with bioinformatics to mine public data sets, To or analyze results. develop hypotheses, we amplify our ability to do bioinformatics, BETSY, have developed an artificial intelligence, that can automatically plan and execute these It is a presenting us with finished results. tasks, backward-chaining expert system that leverages a knowledge base containing descriptions of common bioinformatics algorithms. PRECISION BIOMEDICINE FOR PRECISION CENTER 48 • IMMPACT REPORT CENTER FORPRECISIONBIOMEDICINE Virulence factorregulationgoverningbacterial •Virulence •Molecular targetingofnodalinaggressive RESEARCH PROJECTS current clinicalcancertherapy. synergistic performanceincombinationwith signaling, whilebuildingastrongdatasetonits is todeliveraninnovativedrugtargetNodal breast cancertoassessitsefficacy. Ourgoal translationalanimalmodelsof using relevant specifically targetstheNodalpathwayandare anovelantibodyagent,have developed which cancer aggressivenessanddrugresistance. We cancer cellstemnessandcausingincreased ofexpressioncorrelatingwith with highlevels member, isoverexpressedinbreastcancer, cancer phenotypes. Nodal, a TGFβ family family whichareassociatedwithaggressive of the Transforming GrowthFactorBeta(TGFβ) laboratory isaddressingtheroleofmembers peutic approachesincancertreatment, our signalingpathwaysfornovel thera- relevant disease. with clinicaldiagnosisorintheremovalof clinical applicationstohelpguidephysicians imaging equipment, theseagentshavedirect and bacterialinfection. Combinedwithmodern inimagingcancer agents withfocusedefforts antibodybased diagnostic lab alsodevelops inantibodyengineering,cal achievements our vantage ofantibodyspecificityandtechnologi- that governgrampositiveinfection. Taking ad- standing ofbacterialphysiology, andthefactors instrumental inhelpingtoimproveourunder- antibodies designedbyourlabhavebeen research applications. As basicresearchtools, for bothbasic, diagnostic, andtranslational target disease, antibodiesarepowerfultools infection. breast cancer. Finally, withemphasisontargetingclinically Engineered torecognizeandspecifically Assistant Professor Barrett R.Harvey, PhD house generatedmonoclonals. resonance analysisdemonstrating poorNodalbindingamong commercial antibodiescomparedtoin analysis ofPyMTtumor labeledwithanti-Nodalantibodyforprimary detection. C. Surfaceplasmon A. Western blotanalysisofmouse breastcancerPyMT, and4T1tumorcells. B. Immunohistochemical septum ofdividingbacterialchains. incellwallcleavage.important Beads(designatedbyredarrows)denote AtlA localizationatpolesand Bacterial chaining, thoughttoencouragecolonizationandinfectionisregulatedby AtlA, anenzyme and itsroleinvirulencefitness. Gao, P.; Functional studiesofE. faecalisRNaseJ2 2017. PMID:29049345 10.1371/journal.pone.0186706. eCollection PLoS One. 2017Oct19;12(10):e0186706. doi: Montealegre, M.C.;Murray, B.E.;Harvey, B.R. Stinemetz, E.K.;Gao, P.; Pinkston, K.L.; AtlA septallocalizationandcellseparation. AtlA, bythezinc-metalloprotease, GelE, impacts Processing ofthemajorautolysinE. faecalis, KEY PUBLICATIONS and infectiousdisease oftherapeuticsanddiagnosticstargetingcancer Development John S. DunnResearchScholarI 30445491 model.” Pathog Dis. 2018Nov1;76(8). PMID: valve infectioninaratinfectiveendocarditis antibody reducesEnterococcusfaecalisaortic B.R.; Murray, B.E. “Anti-Ace monoclonal Singh, K.V.; Pinkston, K.L.;Gao, P.; Harvey, 28384222 pone.0175212. eCollection2017. PMID: 6;12(4):e0175212. doi:10.1371/journal. van Hoof, A.; Harvey, B.R.2017Apr PLoSOne. Pinkston, K.L.;Bourgogne, A.; Murray, B.E.; IMMPACT REPORT • • • • 49 Chen, R.; Lai, L.A.; Sullivan, Y.; Wong, M.; Wong, Y.; L.A.; Sullivan, R.; Lai, Chen, V.G.; L.; Pillarisetty, J.; Jung, L.; Riddell, Wang, “Disrupting glutamine S., Pan, T.A.; Brentnall, gemcitabine- metabolic pathways to sensitize Scientific Reports, resistant pancreatic cancer”, 7(1):7950. 2017, R.E.; Petersen, R.; Brand, E.N.; Chen, Nigjeh, J.K.; Feng, Eng, P.D.; von Haller, S.T.; G.M.; Chari, “Quantitative S., Pan, T.A.; Q.; Brentnall, Yan, Z.; proteomics based on optimized data-indepen- of Journal dent-acquisition in plasma analysis”, 16(2):665-676. 2017, Proteome Research. LAB MEMBERS PhD Post-doctoral fellow: Hong Peng, Research coordinator: Li Li Research associate: Xin Li Alisha Kashyap Undergraduate student: basic, translational and clinical applications. basic, glycation and other PTMs in malignances, glycation and other PTMs in malignances, chronic diabetes and neurological diseases, inflammation. therapeutic targets in pancreatic ductal therapeutic targets in pancreatic especially those adenocarcinoma (PDAC), such as associated with cancer precursors, (PanIN) pancreatic intraepithelial neoplasia and pancreatic mucinous neoplasms (IPMN, MCN). KEY PUBLICATIONS J.K.; Eng, T.A.; R.; Brentnall, H.; Chen, Peng, “Predictive proteomic S., Pan, V.J.; Picozzi, signatures for response of pancreatic cancer Clinical patients receiving chemotherapy”, 17;16:31. 2019, Proteomics. tissues are broadly involved in many aspects of tumorigenesis Differential proteins identified in PDAC to facilitate cancer progression. •Innovation of proteomic technologies for Investigation of protein glycosylation, •Investigation of protein glycosylation, Deciphering proteome alterations associated with diseases associated proteome alterations Deciphering RESEARCH PROJECTS and •Discovery of protein biomarkers Sheng Pan, PhD Sheng Pan, Center Proteomics Service Translational and the Clinical / Director, Associate Professor Proteins are essential functional biomolecules that are involved in all aspects of cellular physi- ologic activities and have been important tar- gets for drug development and early detection especially quantitative Proteomics, of diseases. basic, has been a vital tool in proteomics, providing and clinical research, translational, a unique avenue to investigate disease- associated molecular alterations at a functional Proteome alterations that are associated level. with diseases may include changes in protein post-translational modi- sequence, expression, with and protein interactions fications (PTMs), may all which proteins and other biomolecules, In lead to a malfunction of cellular processes. proteomic mass spectrometry based our lab, technologies are applied to study cancer and These studies are carried out other diseases. better such as aiming to with various goals, understand the molecular mechanisms underly- in to investigate changes ing tumorigenesis, identify to PTM status associated with diseases, cancer associated protein biomarkers or thera- or to interrogate microbiome peutic targets, The samples involved in our studies dysbiosis. include a variety of research and clinical and blood, including tumor tissues, specimens, as well as isolated cells other bodily fluids, our Currently, from various clinical specimens. main disease focuses are pancreatic cancer In addition, and other GI-tract malignances. our lab also sup- through collaborative efforts, ports proteomic study of neurological diseases, degenerative diseases, chronic inflammations, and therapeutic drug infectious diseases, bioinformat- Mass spectrometry, development. and chemical biology are systems biology, ics, important components in our study. PRECISION BIOMEDICINE FOR PRECISION CENTER 50 • IMMPACT REPORT CENTER FORPRECISIONBIOMEDICINE showed thatourESTA1 andCD44aptamers tuberculosis. We recently(Leonardetal. 2017) as Dengue2virus, C. difficileinfectionsand ers inschizophrenia(Walss-Bass etal, 2019) • marrow. targeting theendotheliumoflymphomain bone • tumor effectsincombinatorialtherapy. can reducecanceraloneandenhancesanti- • effects inovariancancer. vascular maturationtoenhanceanti-tumor aptamer directeddeliveryofsiRNAimproves • increased survivalrates. breast cancermetastasisandleadingto cancer siRNAtothebonemarrow, reducing • ing: aptamer-related researchhasshownthefollow- method issafeinpreclinicaltesting. Ourrecent cancer. Furthermore, wehavealsoshownour and moreimportantly, thespreadofmetastatic aptamer targetedapproachreducestumorsize, or drugslikePaclitaxel. We haveshownthatour with chemotherapeuticagentssuchassiRNA when usedincombinationtherapytogether However, moreeffective DNAaptamersareeven reduce cancerinadose-dependentmanner. and ovariancancer. SuchDNAcangreatly DNAaptamerstargeting breast have developed disease fightingparticles. forasustainedreleaseofthe silicon particles canalsobeloadedintolarger Such particles anti-cancer agentstoactasaone-twopunch. containing used aloneorascomplexparticles attachments (X-aptamers). X-aptamerscanbe modified DNAjoinedtodrug-likeorprotein-like create harshsideeffectsforpatients. We use Current treatmentsareoftenineffectiveor or infectiousorganisms, suchastuberculosis. thatattackcancer particles agents andsmart Other projectstargetinfectiousagentssuch biomark- X-aptamers canbeusedtodevelop 3, aptamers(Fig Developed Liuetal. 2018) Our AXL aptamer (Kanlikiliceretal., 2017) Our Annexin A2 (Mangalaetal., 2016) ESTA1 directedanti- multistageparticles -Inrecentyearswe Aptamer Development targeting The focusofmylabistodevelop Enhanced deliverytotumors. Associate Professor David Volk,PhD Selecting aptamerstargetingmyeloid-derivedcellsinbreastcancer. •Software toanalyzehowLymedisease X-aptamerstargetingother new •Developing toattack particles ofsmart •Development RESEARCH PROJECTS post-infection deficits. cause long-termLymediseaseinfectionand disease. Suchantigenicvariationisthoughtto in B. burgdorfori infections, thecauseofLyme sequence changesduringrecombinationevents working onsoftwarefortheanalysisofDNA use graphicaluserinterfaces. We arecurrently a completelyautomatedprogramwitheasy-to- therefore developed Aptaligner (Luetal. 2014), of next-generationsequencing(NGS)data. We novelsoftwarefortheanalysis and todevelop the labistoprovidebioinformaticssupport M. tuberculosis (Tb)burden. enhancing theimmunesystemandreducing phages infectedwithM. tuberculosis, thereby tomacro- deliver mesoporoussiliconparticles Targeting cancerwithX-aptamersandnanoparticles escapes hostimmunesystems. diseases. breast andovariancancers. - Software Development Another focusof Research associate:XinLi, MS LAB MEMBERS Informatics (2019)94:103192. service.center projectsgobeyond JBiomedical D.; andBernstam, E.V. Bioinformaticsservice Chang, J.T.; Volk, D.E.; Gorenstein, D.G.; Steffen, Genes (2019)10:297. derived cellsinmurinemodelsofbreastcancer. Shen, H. Tracking biodistributionofmyeloid- X.; Ramirez, M.R.;Zu, Y.; Lokesh, G.; Volk, D.E.; Li, J.;Mai, J.;Hinkle, L;. Lin, D.; Zhang, J.;Liu, (2019) 5:52–59. schizophrenia. MolecularNeuropsychiatry, and ApoB inbloodaspotentialmarkersfor Volk, D.E. identifiesC4A X-aptamertechnology Gorenstein, D.G.; Roberts, D.L.; Velligan D.; Walss-Bass, C.;Lokesh, G.L.R.;Dyukova, E.; KEY PUBLICATIONS IMMPACT REPORT • • • • 51 different X-aptamers). different X-aptamers). 8 Proteome bound to bead-X- aptamer were sorted based on fluorescence intensity at each channel by a two- ARIA II flow color BD FACS cytometer (B). X-aptamer based proteome Patient plasma selection. and health donor plasma Alexa cells were labeled with Alexa Flour Fluor 488 or mixed respectively (A), 647, and then incubated with X-aptamer beads library (10 Maiti, S.N.; Bulayeva, N.; Choi, H.J.; Dorniak, H.J.; Dorniak, N.; Choi, S.N.; Bulayeva, Maiti, - Lopez-Beres K.P.; L.J.; Rosenblatt, Cooper, P.L.; Improving A.K. Sood, D.G.; Gorenstein, G.; tein, RNAs vascular maturation using noncoding chemotherapy. increases antitumor effect of doi: 10.1172/ 2016;1(17):e87754. JCI Insight. PubMed PMID: 27777972; jci.insight.87754. (*equal contributions) PMCID: PMC5070952. X. Yang, D.L.; West, X.; C.H.; Li, H.; Lam, Wang, Biochimie. Selection of PD1/PD-L1 X-Aptamers. pii: S0300-9084(17)30230-4. 2017 Sep 11. [Epub doi: 10.1016/j.biochi.2017.09.006. ahead of print]; PMID: 28912094 G.L.; Lokesh, D.E.; Volk, X.; H.; Li. Wang, A.M.; L.; Nick, M.A.; Li, Elizondo-Riojas, D.G. Gorenstein, K.P.; Rosenblatt, A.K.; Sood, Morph-X-Select: Morphology-based tissue aptamer selection for ovarian cancer biomarker 2016;61(5):249-59. Biotechniques. discovery. PMID: PubMed doi: 10.2144/000114473. 27839510; PMCID: PMC5136366. Thiviyanathan, C.H.; H.; Lam, Wang, G.L.; Lokesh, X- D.E. Volk, D.G.; N.; Gorenstein, Ward, V.; Methods Mol aptamer selection and validation. doi: 10.1007/978- 2017;1632:151-174. Biol. 28730438. PubMed PMID: 1-4939-7138-1_10. LAB MEMBERS Research associate: Xin Li Andrea Costello Medical student: ated nanoparticle–drug delivery. cellular carcinoma. As aptamers can serve as an importantAs aptamers can serve as an Aptamer-mediated targeted imaging. •Aptamer-mediated targeted imaging. KEY PUBLICATIONS Wu, D.; H.; *Jiang, L.S.; *Wang, *Mangala, Lokesh, D.E.; Volk, A.; Somasunderam, S.Y.; X.; Haem- Yang, S.; X.; Pradeep, G.L.; Li, A.S.; C.; Nagaraja, M.; Rodriguez-Aguayo, merle, R.; Li, E.; Bayraktar, R,; Bayraktar, Rupaimoole, K.M.; C.; Gharpure, W.; Ivan, Hu, T.; Tanaka, L.; X.; Zhang, V.; Thiviyanathan, M.H.; McGuire, Targeted cancer therapy with aptamer medi- •Targeted and outcome prediction for HCC patients. and outcome prediction for aptamer ligand, category of molecular targeting targeted imag- mediated targeted therapy and ing offer a unique opportunity for selective or and drugs, delivery of therapeutic siRNA Several modified aptamers imaging agents. have been successfully identified in our lab for A2, Annexin such as further targeted studies, Those Vimentin, and Thy1. CD44, PD1, PD-L1, selected aptamers have great application potential in targeted drug delivery or targeted By conjugating the specific aptamer imaging. with nanoparticles that are loaded with drug delivery we demonstrated specific or siRNA, and targeting to ovarian cancer after systemic administration in vivo. RESEARCH PROJECTS •Proteomics biomarker discovery for hepato- Cancer biomarker discovery and targeted therapy and targeted discovery Cancer biomarker Hongyu Wang, MD, PhD MD, Wang, Hongyu Assistant Professor Biomarker discovery and targeted therapy are Aptamer impotent parts of precision medicine. mediated biomarker discovery and targeted therapy are attractive approaches for precision Aptamers are single- cancer treatment. stranded oligonucleotides with high affinity and DNA specificity to the target molecules or cells. aptamers have many significant advantages over monoclonal antibodies in terms of feasibil- and facile non-immunogenicity, low cost, ity, modification for various applications. created a systematic biology approach that We combines a bead-based modified aptamer library with flow cytometry sorting and mass spectrometry to identify proteomics biomarkers. with beads- plasma were incubated Patients’ X-aptamer library and sorted by flow cytometry based on fluorescence intensity (Figure1). we selected a panel Using this approach, of prognostic biomarkers for hepatocellular carcinoma (HCC) patients under Lipiodol-based treat- transarterial chemoembolization (TACE) imaging In combination with quantitative ment. we will integrate blood biomarkers analysis, with quantitative imaging features to establish a non-invasive platform for precision treatment PRECISION BIOMEDICINE FOR PRECISION CENTER 52 • IMMPACT REPORT T CENTER FORSTEMCELL AND REGENERATIVE MEDICINE these studiesis development oftherapiesthat tissue-resident stem cellsoriPSCs.Thegoal of correct thedisease-causing mutationsin either recently developed geneeditingtechnologiesto inherited disease,Centerfaculty are utilizing therapeutic benefit. to bestdeliver andmaintainsuchcells/tissuesfor –aswell ashowblood, lung,muscle,andcartilage tissues oftherapeuticinterest includingneural, iPSCsintovariousmethodologies toconvert cells/ are seekingtodevelop efficientand robust the humanbody. Faculty withintheCenter the various celltypesandtissuespresent within and inprinciple,maybespecificallyguidedinto from easilyobtainedcellsfrom anyindividual patient-specific stemcellsthatcanbegenerated induced pluripotentstemcells(iPSCs).iPSCsare therapeutic interest toCenterinvestigators is disease. Asecondclassofstemcellssignificant due tonormalcellturnover, aging,injury, or in active regeneration ofcellsandtissueslost bone marrow, intestine, andlungare involved present throughout lifeinvarious organssuchas these are tissue-resident stem cells;suchcells for suchtherapeuticapplications.Thefirstof cells underactive investigation withintheCenter consequence ofnormalaging,injury, ordisease. employed toreplace cellsandtissueslostasa healthy stemcells,ortheirderivatives, canbe be effectively translatedintotherapiesin which fundamental understandingofstemcellsmay the hopesofregenerative medicineisthatthis of tissuesandorgansthroughout life.One of normal development aswell asinmaintenance cells ismotivated by theiressentialrole inboth health anddisease.Theinterest inhealthystem stem cellsinboth of properties biological studies ofthe experimental focused on (CSCRM) are Medicine Regenerative Stem Celland the Centerfor and traineesof For patientspresenting withgenetically There are atleasttwodistinct classesofstem staff, research he faculty, University Chair The C. Harold andLorine G. Wallace Distinguished Professor andCenter Director Brian R.Davis, PhD please donothesitatetocontactme. of principleandeventual externalgrantfunding. stage advances required fordemonstratingproof and continuetobeessentialinseedingtheearly endowed chairs,gifts,orpilotgrants,have been to Centerinvestigators, eitherintheformof Importantly, philanthropic fundsmadeavailable STARs Program, Mission Connect,andothers. Fibrosis Foundation, University of Texas Rising Prevention Research Institute of Texas, Cystic of Health, ofDefense, Department Cancer various sources includingtheNational Institutes funding forthesestudieshasbeenreceived from role ofstem cellsincancer. Competitive grant lung, andblood,aswell aselucidatingthe such asspinalcord, brain,muscle,cartilage, therapeutic value ofstemcellsforrepairing tissues examples ofCenterfacultyexploringthepotential such aslymphoma. cells intheinitiationandmaintenanceofcancers Center facultyare interrogating therole ofsuch typicallyassociatedwithstemcells. properties presence withincancersofcellshavingspecific them backintothesamepatient. corrected stemcellsorcells/tissuesderived from own stemcells,thendelivering eitherthe include correcting themutationsinapatient’s If Imayprovide anyadditionalinformation, In thepagesfollowing you willfindseveral Finally, there isincreasing evidenceforthe IMMPACT REPORT • • • • 53 W. Zacharias; M. Ochs; K. Traber; L.J. Quinton; Traber; L.J. Ochs; K. M. Zacharias; W. Wambach; White; J. Davis; F.V. B.R. Crane; A. Gut- Morrisey; S.H. Cole; E.E. Whitsett; F.S. J.A. Differentiation Kotton. Beers; D.N. tentag; M.F. cells into functional of human pluripotent stem Cell Stem Cell lung alveolar epithelial cells. 21:1-17. 2017, Mishra; N. A. Wei; H. Tarnawsky; Kobayashi; S. M. Wu; B. Davis; J. B. Wenzel; Azevedo Portilho; P. Hemogenic endothelial Yoshimoto. Hadland; M. cells can transition to hematopoietic stem cells through a B-1 lymphocyte-biased state during Stem Cell maturation in the mouse embryo. 13:21-30. Reports 2019, LAB MEMBERS Avila, John M. Post-doctoral fellows: Dr. Shingo Suzuki Dr. Cristina Barilla, Dr. Graduate Anirudhan students: Varada Nadine Dr. Crane, Ana M. Research staff: Dr. Haipeng Xue Matthias, Aldrich Syndrome patients. Cystic Fibrosis patient-specific iPS cells. cells from Cystic Fibrosis patients. KEY PUBLICATIONS Driver; D. I. Jacob; A. Kramer; Hawkins; P. F. Crane; A.M. Skvir; Benson; N. Thomas; K.A. Nguyen; B.G. Hollenberg; S. A.N. Kurmann; A.A. Guttentag; Huang; S. Khalil; S.X.L. A.S. Wong; Kotton. Davis; D.N. Shannon; B.R. Rock; J.M. J.R. Prospective isolation of NKX2.1-expressing hu- man lung progenitors derived from pluripotent of Clinical Investigation Journal stem cells. 127:2277-2294. 2017, McCauley; Hawkins; K.B. Morley; F. Jacob; M. A. Weaver; M. T.E. Heins; C-L Na; Jean; H. J.C. Kook; Russo; S. Hinds; S.J. A. Hurley; K. Vedaie; Deriving airway epithelium from induced pluripotent stem cells. Schematic of differentiation protocol A. Derived airway epithelium B. Derived airway epithelium exhibits CFTR function C. Correction of blood stem cells from Wiskott- from •Correction of blood stem cells Derivation of airway basal stem cell from • Derivation of airway basal stem Genetic correction of stem cells for treatment of inherited lung of stem cells for treatment of inherited Genetic correction and blood diseases RESEARCH PROJECTS cells and iPS •Correction of airway basal stem Brian R. Davis, PhD Davis, Brian R. Professor Regenerative Medicine Center for Stem Cell and Director of the Chair Distinguished University Wallace Lorine G. Harold and C. Dr. Davis’ laboratory has as its primary objec- laboratory has as its primary Davis’ Dr. tive the sequence-specific genetic correction of mutations in the chromosomal DNA of induced pluripotent stem (iPS) cells and/or tissue- specific stem cells derived from patients with inherited disorders affecting the lung or blood is being pursued with the ultimate This system. goal of developing stem cell-based therapeutic DNA sequence- have utilized We approaches. specific nuclease-mediated homology directed repair to correct the most common genetic mutations in iPS cell lines derived from patients with Cystic Fibrosis – and have demonstrated genetic and functional correction in lung epithelial cells derived from these corrected lung-specific have introduced We iPS cells. fluorescent reporters into iPS cells and utilized to specifically isolate early lung progenitors and then airway basal stem cells for purposes of molecular and functional characterization. One of our objectives is to employ CF patient- specific iPS cell-derived lung epithelium for testing sensitivity to specific CF drugs -- in order to facilitate a personalized therapeutic are also presently utilizing the We approach. fore-mentioned gene correction methodologies to correct the CF mutations in tissue-specific stem cells directly obtained from CF patients. The second major project in the laboratory focuses on the site-specific correction of gene mutations responsible for inherited blood Wiskott-Aldrich Syndrome disorders such as the Again, a primary immune deficiency. (WAS), we are seeking to correct the disease-causing mutations in patient-specific blood stem cells. the ultimate WAS projects, In both the CF and objective is the delivery back to patients of their only differing from own lung or blood stem cells, the original stem cells by the genetic correction of the relevant mutation. STEM CELL AND REGENERATIVE MEDICINE REGENERATIVE AND CELL FOR STEM CENTER 54 • IMMPACT REPORT CENTER FORSTEMCELL AND REGENERATIVE MEDICINE central nervoussystem. However, thenumberof for thetreatmentoftraumatic injuriestothe (hiPSC) offerpotentially autologouscellsources timized. Humaninducedpluripotentstemcells cellsourcesalsoneedtobeop- cally relevant for theexpansionanddifferentiationofclini - matrices towidespreadclinicaluse, protocols rat modelsofspinalcordinjury. across spinalcordlesioncavitiesinsubacute facilitate theextensionofaxonsfromhost studies havefocusedonformulatingmatricesto better thantraditionalmatrices. Preliminary far tissuedevelopment ronment andsupport begin toemulatethenativetissuemicroenvi- trolled architecture, these hybridmatricescan with additionalbioactivesignalingandcon- cellular response, respectively. When combined and batch inconsistencyinscaffoldproperties namely lackofbioactivesignalingandbatchto polymers, whilemitigating theirdisadvantages, sponse) andnatural(nativebioactivesignaling) (consistency infabricationandcellularre- maximize theadvantagesofbothsynthetic into advancedhybridmatrices. These matrices ing combinatorialmethods, areintegrated they peptide concentrationshavebeenidentifiedus- mechanical properties, andbioactivesignaling (porosity, featuresize, fiberalignment, etc.), tissue. Onceoptimalcomposition, architecture and integrationwiththesurroundinghost extracellular matrixfacilitatetissuerepair seek tounderstandwhichaspectsofthenative implantation intopatients. thecellsafter stem celltherapyandtosupport cellsourcesforusein of clinicallyrelevant to optimizescaffolddesignfortheexpansion engineering approaches, thelaboratoryseeks chemistry, andmaterialscience. Utilizing from cell, molecular, andstemcellbiology, interdisciplinary approachinvolvingtechniques brain injury, andstroke. The laboratoryusesan treatments forspinalcordinjury, traumatic biomaterialstobeusedinclinical developing In order to advance biomaterial cell support In ordertoadvancebiomaterialcellsupport By examiningcell-materialinteractions, we The researchinmylaboratoryfocuseson blue. Scalebars=100µm. (green) encapsulated inthehydrogelfor1weekundergoingneural differentiation. Nuclearstainingis response ofhumaninduced pluripotentstemcellderivedneural stemcellcytoskeletalorganization Schematic ofhydrogelwithacontinuous gradient intwopeptideconcentrations(IKVAVandMMP) • • RESEARCH PROJECTS onhiPSClineagechoice.properties gradient tostudytheeffectofmechanical of hydrogelswithcontaininga Young’s Modulus the covalenttetheringofproteinstosurface from hiPSC. Preliminarystudieshavefocusedon stem cellsandoligodendrocyteprogenitor cell culturesurfacesfordifferentiationofneural culture systemstooptimizetwodimensional to extendourknowledgeofthreedimensional to hiPSCdifferentiation. The laboratoryseeks have notbeenstudiedsignificantlyinrespect significantly affectcellulardifferentiationbut of thecellculturesurfacehavebeenshownto Both biochemicalandmechanicalproperties rent differentiationprotocolsisextremelylow. viable cellsfortransplantproducedfromcur- injuries engineeringapproachesforthetreatmentofCNS Tissue Assistant Professor Laura A. SmithCallahan, PhD injury. mature celltypesaftercentralnervoussystem the host, andmaturationtowardfunctional promote celltherapysurvival, integrationwith Modulation ofcellularenvironmentinvivoto linages usingcombinatorialapproaches. to neuralprogenitorcellstherapeutic direct humaninducedpluripotentstemcells Optimization ofsubstratesandmatricesto Post-doctoral fellows: T. HiranPerera, XiLu LAB MEMBERS 3(5):776-781,Science &Engineering. 2017. peptide His-Ala-Val-Asp-Ile. ACS Biomaterials concentration gradientofn-cadherinderived methacrylate hydrogelscontainingacontinuous neural differentiationonpolyethyleneglycoldi- stem cellderivedneuralsurvivaland Smith Callahan, L.A. Humaninduced pluripotent T.H.; Kurosu, Y.E.; Ravivarapu, K.;Mosley, M.C.; Lim, H.J.;Khan, Z.; Wilems, T.S.; Li, X.;Perera, 824-833, 2017. Biomedical MaterialsResearch: Part A. 105(3): continuous Young’s Modulusgradient. Journal of on apolyethyleneglycolhydrogelscontaining pluripotent stemcellderivedneuralcells and neuronaldifferentiationofhumaninduced S.; Liu, Y.; SmithCallahan, L.A. Neuriteextension Mosley, M.C.;Lim, H.J.; Chen, J.; Yang, Y-H.; Li, Biomaterialia. 71:271-278, 2018. hydrogels throughpeptideinteraction. Acta degradable polyethyleneglycoldimethacrylate Mechanical stabilizationofproteolytically T.S.; Ravivarapu, K.;SmithCallahan, L.A. Lim, H.J.;Khan, Z.;Li, X.;Perera, T.H.; Wilems, KEY PUBLICATIONS IMMPACT REPORT • • • • 55 progenitors derived from integration-free iPSCs progenitors derived from integration-free doi: Stem Cell Res. 9:55-64. for SCI therapy. PMID: 28073086 10.1016. Y.Y.; H.; Zheng, Yan, R.; Cuevas-Diaz Duran, Q.L.;* Cao, D.H.; Kim, R.; Grill, X.F.; Huang, The systematic analysis (2017). J.Q.* Wu, and of coding and long non-coding RNAs in the sub-chronic and chronic stages of spinal cord PMID: doi: 10.1038. 7:41008. Sci Rep. injury. 28106101 (* co-corresponding authors). C.L.; Fan, X.B.; P; Qi, Bu, Y.Y.; X.X.; Zheng, Cheng, Apoli- (2018). Q.L. and Cao, D.H.; Kim, F.Q.; Li, poprotein E as a novel therapeutic neuroprotec- tion target after traumatic spinal cord injury. Experimental Neurology 299: 97-108. LAB MEMBERS Yiyan Zheng Post-doctoral fellow: Graduate student: Chrystine Gallegos Research associate: Haipeng Xue Undergraduate student: Matthew Carey cells for spinal cord injury and stroke. regeneration and functional recovery after SCI gramming of astrocytes after SCI. and chemogenetic approach for SCI repair. KEY PUBLICATIONS KEY PUBLICATIONS Schmitt, H.P.; S.L.; Xue, Li, Y.Y.; Zheng, Y.; Liu, Y.Y.; J.Q.; Zhang, Wu, G.W.; K.; Hergenroeder, Human neural (2017). Q.L. and Cao, D.H.; Kim, Astroglial scar formation after traumatic spinal cord injury in double-transgenic mice of GFAP-cre/Ai9. •Human iPSC-derived neural stem or precursor •Combinatorial approaches to promote axonal Treating neuropathic pain by in vivo repro- •Treating Stem cells for neurological diseases for neurological Stem cells astrocyte inhibition precursor cells will decrease The newly to promote axonal regeneration. cells could reprogrammed neuronal precursor SCI or stroke. replace the lost neurons after work synergistically These two mechanisms may recovery after SCI to promote great functional Our long-term goal is to develop novel or stroke. stem cell-based therapies to treat human SCI or stroke. RESEARCH PROJECTS •In vivo reprogramming of reactive astrocyte Qi Lin Cao, MD Qi Lin Cao, Professor Transplantation of neural stem cells (NSCs) Transplantation is proved a promised therapeutic approach to promote functional recovery after neurological (SCI) and including spinal cord injury diseases, there is no consensus as to However, stroke. Human which NSC resource is optimal for SCI. central nervous system stem cells isolated from fetal cadaver brain tissue and neural progenitor cells derived from human embryonic stem cells (hESCs)-derived have been approved for these However, clinical trials for SCI patients. cells are associated with ethical controversy hESCs Cells derived from and graft rejection. have additional risk of teratoma formation. Human induced pluripotent stem cells (hiPSCs) are recently developed remarkable pluripotent, somatic adult from reprogrammed cells ESC-like cells by over-expression of four developmental/ Compared pluripotency transcription factors. additional hiPSCs offer significant with ESCs, advantages in terms of availability of source material without ethical concerns of embryo generate iso- and especially the ability to use, grafts without the need of immunosuppression. have developedWe protocol to differentiate and neuronal precursor cells or glial pre- purify NSC, Our results show that cursor cells from hiPSCs. hiPSC-derived NSCs can proliferate over long into differentiate induced to and be in vitro time astrocytes and oligoden- functional neurons, hiPSC-derived NSCs can Importantly, drocytes. survive and differentiate into both neurons and glias after transplantation into the contused spinal cord and promote functional recovery. These studies suggest that transplantation of hiPSC-derived NSC is an effective therapy to preserve and restore neurological functions. we are testing the therapeutic ef- Currently, neuronal ficacy and long-term safety of NSCs, or glial precursor cells to identify the optimal we are Recently, cell graft for SCI and stroke. testing whether we can directly reprogram the astroglial cells in the injured spinal cord or Astroglial scar are the stroke brain into neurons. In situ major inhibitor for axonal regeneration. reprogramming active astrocytes into neuronal STEM CELL AND REGENERATIVE MEDICINE REGENERATIVE AND CELL FOR STEM CENTER 56 • IMMPACT REPORT cell productionforuseinourclinicalprotocols. treatments. These facilitiesallow clinical grade ties thatenableustotranslatediscoveryinto which arecGMPandcGTPcellprocessingfacili- tory andtheHoffbergerStemCellLaboratory, beds. use invivomodelsofinjuryandvitrotest inquestion.specific tothepathophysiology We delivery, aswelltiming), whichmaybevery regimens (numberofcells, type, androute of these typesofdatatohelpusdeterminedosing macrophage phenotypeinthebrain. We use upregulation andmodulationofthemicroglia/ reticuloendothelial systemhaveresultedin Treg term. Cell-cellinteractionsintheperipheral significant engraftmentinthebrainlong cellular therapieshavebeensuccessfulwithout the innateimmuneresponseto TBI andhow We havebeeninterestedinthemodulationof injuries, principallytraumaticbraininjury(TBI). the useofcellulartherapiesforneurological CENTER FORSTEMCELL AND REGENERATIVE MEDICINE Our teamdirectstheGriffinStemCellLabora- Our currentresearchprogramfocuseson George andCynthiaMitchellDistinguishedUniversityChair Professor Charles Cox, Jr., MD innate immunity Naama Toledo-Furman, PhD, flow cytometry/ Amit Srivastava, PhD, assistantprofessor Supinder Bedi, PhD, assistantprofessor Cecilia Martin, PhD, researchassociate Prabhakara,Karthik Srresearch assistant Katherine Ruppert, PhD, Srresearchassociate Scott Olson, PhD, assistantprofessor therapy Mitchell George, MD, TBI clinicalandcell Louis Carrillo, MD, TBI clinicalandcelltherapy therapy Akshita ‘Jade’ Kumar, MD, TBI clinicalandcell Ca,Yidao -programmeranalyst Joiya Arrington, MSN, RN, TBI clinical Kosmach,Steven MSN, RN, CCRC-TBI clinical LAB MEMBERS PMCID: PMC5367945 Cells 35:1065-1079, 2016. PMID:27800660, using bonemarrowmononuclearcells. Stem Treatment adulttraumatic braininjury ofsevere Aisiku, I.;Choi, H.A.;Holcomb, J.B.;Kitagawa, R. F.; Dash, P.K.; Pedroza, C.;Lee, D.A.; Worth, L.; Romanowska-Pawliczek,Jackson,M.L.; A.;Triolo, Ewing-Cobbs, L.;Juranek, J.;Savitz, S.I.; Cox, C.S.;Hetz, R.A.;Liao, G.P.; Aertker, B.M.; ADMET &DMPK. 3(3):182-189, 2015. permeability intraumaticbraininjuryresearch. son, S.D.; Cox, C.S. Assessing bloodbrainbarrier K.S.; Smith, P.A.; Hetz, R.A.;Xue, H.;Bedi, S.;Ol- Liao, G.P.; Aertker, B.A.;Kota, D.J.; Prabhakara, 2017. PMID:28624058 injury: aMeta-Analysis.JSurg Res214:38-48, ical progenitorcelltherapyintraumaticbrain Jackson, M.L.;Srivastava, A.; Cox, C.S. Pre-clin- KEY PUBLICATIONS •Imaging ofmicroglialactivationinvivo. •Novel deliverysystemsforstemcellsin •Amniotic fluidderivedMSCsforthetreatment •IND-enabling studiesusing APCs fortrau­ ofPhase1and2Clinical •Development Trials RESEARCH PROJECTS Cellular therapiesforneurologicalinjury neurological injury. bypass/hypothermic circulatoryarrest. diseaseandcardiopulmonary genital heart of neurologicalinjuryassociatedwithcon- brain injury. traumatic braininjury. using non-ESCstem/progenitorcellsfor matic Stephanie Baca, programmanager Christina Willingham, programmanager Max Skibber, researchassistant Tushar Sharma, scientificprogrammer Kevin Aroom, scientificprogrammer Matteo Costantini, researchassistant Deepa Bhattarai, Srresearchassociate coordinator Romina Gipson-Love, qualityimprovement Sufira Kiran, GMP, QAdirector Fabio Triolo, PhD, GMPcenterdirector Hasen Xue, MD, researchasssociate production. ofanovelbioreactorforstemcell Development IMMPACT REPORT • • • • 57 KEY PUBLICATIONS KEY PUBLICATIONS N.; Servián-Morilla, Matthias, S.D.; Hunt, J.; Wu, R. C.; Darabi, H.; Paradas, J.; Jafar-Nejad, E.; Lo, stem cell Generation of an induced pluripotent patient with a newline (CSCRMi001-A) from a dystrophy (LGMD) type of limb-girdle muscular due to a missense mutation in POGLUT1 (Rumi). 2017 24: 102-105. Sep. Stem Cell Research, J.; Smith Cal- J.; Lo, Wu, S.D.; N.; Hunt, Matthias, Volumetric R. J.; Darabi, Huard, Y.; L.A.; Li, lahan, muscle loss injury repair using in situ fibrin gel cast seeded with muscle-derived stem cells 27: 65-73. Mar. Stem Cell Research. (MDSCs). 2018 J.L.; J.; Ortiz-Vitali, N.; Lo, J.; Matthias, Wu, A Myogenic R. S.H.; Darabi, Wang, A.W.; Shieh, double-reporter human pluripotent stem cell line allows prospective isolation of skeletal 25/7: Nov. muscle progenitors. Cell Reports. 2018 1966-1981. LAB MEMBERS Instructor: Jianbo Wu Research associate: Nadine Matthias degeneration. CRISPR/Cas9 system. recovery potential of hPSCs in the mice mod- els for Duchenne muscular dystrophy (DMD) and muscle mass loss injury. •In vivo gene activation to ameliorate muscle •Gene correction of patient-derived iPSCs using Using stem cells to treat muscle disorders cells to treat muscle Using stem as disorders, PSCs in mice models for muscle regulators of well as identification of novel sgRNA myogenic program using genome-wide Our research team also works library screen. patients with newon derivation of iPSCs from such as LGMD2Z, types of muscular dystrophies as well gene correction of patient-derived iPSCs, as enhancing cell delivery and engraftment in is Our research program the skeletal muscle. currently funded by two NIH grant awards from Arthritis and Musculoskel- National Institute of etal and Skin Diseases (NIAMS) to support these exciting and novel projects. RESEARCH PROJECTS •Evaluation of the engraftment and functional Radbod Darabi MD, PhD MD, Radbod Darabi Associate Professor Muscle stem cells (satellite cells) stained in red in a muscle tissue cross section. Green stain marks Muscle stem cells (satellite cells) stained in red in a muscle tissue cross section. cross sections. myofibers’ Skeletal muscle is the largest tissue in the we are interested to use Here at our center, by using cutting-edge gene Here at IMM, Other major goals of our lab include using STEM CELL AND REGENERATIVE MEDICINE REGENERATIVE AND CELL FOR STEM CENTER various dis- is very prone to body and therefore, disorders Most common types of muscle orders. include gradual muscle deterioration during aging (sarcopenia) or after severe systemic or in diseases (such as heart or kidney failure, are Muscle loss injuries patients with cancer). also very common after accidents or during genetic disorders In addition, combat injuries. of the muscle such as muscular dystrophies are also a major health problem with no definitive these disorders will eventuallyAll of lead cure. to progressive muscle weakness and loss of its these in severe cases, Unfortunately, function. disorders are fatal due to the involvement of heart or breathing muscles. pluripotent stem cells (PSCs) for the treatment the last few During of these common disorders. our lab has developed novel methods for years, myogenic differentiation of induced pluripotent stem cells (iPSCs) as cell therapy in different such as Duchenne skeletal muscle disorders, muscular dystrophy (DMD) and muscle loss injuries. targeting/editing technologies (such as CRISPR/ Cas9) our lab has successfully generated knock- in human stem cell lines for early myogenic allows us to This and MYF5. genes such as PAX7 study the emergence of early myogenic progeni- a crucial step to identify tors from human PSCs, and isolate myogenic progenitors useful for stem These cells cell therapy in muscle disorders. have been tested for the engraftment potential in the mice models for Duchenne muscular dys- which so far have demonstrated superior trophy, engraftment and regeneration potential in the Study of the muscle function treated muscles. recovery after stem cell therapy is another which is currently under exciting goal in the lab, investigation. high throughput screening (HTS) to identify evalua- important pathways for myogenesis, tion of the engraftment potential of human 58 • IMMPACT REPORT severe forms of severe TBI, limitedinformationexists a roleformitochondrial dysfunctioninmore outcome. While studieshavedemonstrated nents, exacerbatetissuedamage, andworsen free radicalsthatcandamagecellcompo - of respiration cangiverisetoincreasedlevels ATP. Inaddition, impairedmitochondrial tion occurs, thebraincannotgeneratesufficient normal function. When mitochondrialdysfunc- of glucosetogeneratethe ATP itrequiresfor andreliesonacontinuoussupply store energy TBI. Unlikeother organs, thebraindoesnot mitochondrial functionaftermoderate-severe utilizationandimpaired decreased energy both humansandinanimalmodels. ing theinfluenceofrepeatedbraininjuryin improvement. To thisend, wehavebeenexamin- treatmentswhichcanofferfunctional develop that occurfollowingconcussioninorderto the molecular, cellular, andstructuralchanges continued researchisrequiredtounderstand brain remainsvulnerabletoasecondinjury, the brainreturnstoitspre-injurystate. As the consequences. Itremainsunknownwhen, orif, rather aprogressivediseasewithlong-lasting concussion isnotasingularevent, but has occurredafteraconcussion. there isnoobjectivewaytoassessifbraininjury fraction ofactualconcussioncases. Currently, tion, theabovestatisticsmayonlyrepresenta seekmedical atten- many ofthesepeoplenever losingconsciousness,sion withoutever and Americans. As apersoncansustain aconcus- incidence ofconcussionisontheriseinolder the numberoffallsinourolderpopulation, the Recently, and duetotheincreaseinlongevity which 87%canbeclassifiedasconcussion. Americans sustainabraininjuryeachyear, of for DiseaseControl, approximately2.6million all agesandsexes. According totheCenters incontactsports,participating butpersons of health problem, strikingnotonlyathletes brain injury, mTBI)hasemergedasamajor CENTER FORSTEMCELL AND REGENERATIVE MEDICINE A large number of studies have reported A largenumberofstudieshavereported It hasbeenrecentlyappreciatedthat Concussion (alsoknownasmildtraumatic Neurotrauma. 36:2147-2152, 2019. after repetitivemildtraumaticbraininjury. J. and Dash, P.K. Carnosicacidimprovesoutcome Zhao, J.;Kobori, N.;Hood, K.N.;Moore, A.N.; Maynard, M.E.;Underwood, E.L.;Redell, J.B.; KEY PUBLICATIONS •To investigatetheconsequencesofmito- •To investigateneurovascularfunctionafter •To identifyhowconcussionaltersneural RESEARCH PROJECTS and improvedcognitiveoutcome. associated withreducedwhitematterdamage These beneficialeffectswerefoundtobe increase ATP-linked mitochondrialrespiration. protonleakageafterrepeated mild reverse TBI with this, wehavefoundthattreatmentswhich increased freeradicalproduction. Consistent been linkedtoinsufficient ATP generationand across themitochondrialmembraneandhas mitochondrial functionandleakageofprotons Maintenance ofaprotongradientiscriticalfor increases protonleakinthehippocampus. injury, butnotasinglemildinjury, significantly Our resultsindicatethatrepeatedmildbrain function inmicesubjectedtorepeatedmild TBI. respiration assaytomeasuremitochondrial gap, tissue weutilizedourrecentlydeveloped repeated mild TBI. To addressthisknowledge on thestatusofmitochondrialrespirationafter Nina andMichaelZilkhaDistinguishedChair, NeurodegenerativeDiseaseResearch Professor Pramod Dash, PhD Concussion andstress-relateddisorders metabolism afterconcussion. chondrial plasticityandalteredbrainenergy concussion. communication. Diagnostic andBiomedicalSciences Dr. CameronJeter: Assistant Professorof MedicineInstitute Ironman Sports pedic Surgery;Director, ConcussionProgramat Dr. SummerOtt: - Associate ProfessorofOrtho group Director,ogy; DementiaandMemoryDisorders Dr. PaulSchulz: Associate ProfessorofNeurol- at MemorialHermannHospital-TMC Medicine; MedicalDirector, EmergencyCenter Dr. ChairmanofEmergency JamesMcCarthy: COLLABORATORS ahead ofprint);2019. pocampal CA1neurons. JNeurotrauma. (Epub content andreducesplacefieldstabilityofhip- brain injurydecreasesspatialinformation X.O.; Moore, A.N.; Dash, P.K. Mildtraumatic M.E.; Kobori, N.;Perez, A.; Hood, K.N.;Zhang, Broussard, J.I.;Redell, J.B.;Zhao, J.;Maynard, Neurotrauma. (Epubaheadofprint);2019. Spreading. and Induces Tau Aggregation C.; Moreno-Gonzalez, I. Traumatic BrainInjury Edwards, G. 3rd.;Zhao, J.;Dash, P.K.; Soto, of print);2019. learning andmemory. ExpNeurol.(Epubahead hippocampal tyrosinehydroxylaseandimpairs of PTEN-inducedkinase1(Pink1)reduces V.; Waxham, M.N.;Moore, A.N.; Dash, P.K. Loss wood, E.L.;Fischer, T.D.; Hood, K.N.;LaRoche, Maynard, M.E.;Redell, J.B.;Kobori, N.;Under- ATP-linked respiration. accompanied byanincreasein This reductioninprotonleakwas the anti-diabetesdrugmetformin. by in protonleakthatisreversed peated mild TBI caused anincrease pects ofmitochondrialfunction. Re- punches showingthevariousas- respiration fromhippocampaltissue Summary dataofmitochondrial J IMMPACT REPORT • • • • 59 pulmonary neuroendocrine cells and SCLC-like pulmonary neuroendocrine stem cells. J Exp tumors from human embryonic 2019 Mar 4;216(3):674-687. Med. Huang; Jie Chen; Hye Kyung Lim; Sarah X.L. Gaspard Kerner; Olivier Gilliaux; Paul Bastard; Kerry Dobbs; Nicholas Hernandez; Nicolas García Hasek; Eduardo Javier Goudin; Mary L. Lorenzo; Priya Lafaille; Lazaro Reino; Fabien G. Kochetkov; Benedetta Bigio; Tatiana Luthra; Soraya Boucherit; Flore Rozenberg; Catherine Adolfo Itan; Yuval Keller; Michael D. Vedrinne; Orange; García-Sastre; Marie Celard; Jordan S. Ciancanelli; Isabelle Meyts; Qian Michael J. Notarangelo; Abel; Luigi D. Zhang; Laurent Hans-Willem Snoeck; Jean-Laurent Casanova; SevereShen-Ying influenza pneumonitis Zhang. J Exp TLR3 deficiency. in children with inherited 2019 Sep 2;216(9):2038-2056. Med. LAB MEMBERS Post-doctoral fellows: Nicolas Focioli-Conti, Nadine Matthias lung cell fate determination using molecular, lung cell fate determination using molecular, genetic and epigenetic approaches. Use patient hiPSC differentiated lung Use patient hiPSC differentiated TLR3 in epithelial cells to test rare mutations as causative for severe influenza infection induced by H1N1 virus. Human pluripotent stem cells for lung regeneration and for lung regeneration stem cells Human pluripotent disease modeling Sarah Xuelian Huang, MBBS, PhD MBBS, Huang, Sarah Xuelian Assistant Professor KEY PUBLICATIONS Kamryn N. Little, Danielle R. Ostrin, Edwin J. Ricardo Sumner, A. Elizabeth Gerner-Mauro, Samantha Ambrosio, Elizabeth Ríos-Corzo, Haruhiko Forcioli-Conti, R. Nicolas Holt, E. Shioko Kimura, Hanash, Sam M. Akiyama, Beta-Catenin Jichao Chen. Huang, Sarah X.L. maintains lung epithelial progenitors after Development (2018) 145, lung specification. dev160788. Unni; Arun M. Asaf Poran; Huanhuan Joyce Chen; Sarah Xuelian Huang; Olivier Elemento; Hans- Generation of Varmus. Willem Snoeck; Harold RESEARCH PROJECTS • of •Understanding the basic mechanisms A. Lung epithelial cells (NKX2.1+) derived from patient hiPSC (P3) carrying TLR3 gene mutation Lung epithelial cells (NKX2.1+) derived from patient hiPSC (P3) carrying A. (bottom panels) are more susceptible to H1N1 viral infection (influenza NP) compared with those human pluripotent stem cell-derived pulmonary neuroendocrine from healthy control (top panels); B. upon the suppres- progenitors formed small cell lung cancer-like tumors in immuno-deficiency mice, keyThe tumor cells express lung and neuroendocrine sion of two tumor suppressor genes RB and P53. NCAM1 and CGRP). ASCL1, markers (NKX2.1, My laboratory is interested in applying human pluripotent stem cell-based human Recently, Realization of stem cell therapy in lung pluripotent stem cells to study the molecular mechanisms of lung cell fate specification in the context of both normal and pathological The long-term goal is translation conditions. of the acquired knowledge into prevention and treatment of currently not curable lung lung diseases are among the The diseases. Lower respira- leading causes of death globally. chronic obstructive pulmonary tory infections, account for and lung cancer together disease, approximately 9 million deaths annually world- burden, Despite the huge lung disease wide. we still have very limited understanding of the pathogenic mechanisms responsible for these is a lack of and consequently there diseases, successful therapeutic approaches. model has emerged as a novel system for The need for such studies of human diseases. a system stems from the limitations of the exist- ing animal experimental models which fall short in demonstrating concordance with human experimental approaches In addition, studies. utilizing primary human adult lung cells are inadequate in large part due to the limited availability of lung tissue from healthy subjects. diseases relies on the successful generation As a first, of clinically applicable cell types. we have previously critical step in this direction, developed a step-wise differentiation strategy that directs human pluripotent stem cells to become different types of upper (airway) and lower (alveoli) respiratory lung epithelial cells Nat Biotechnol at large quantities (Huang et al. As a proof of principle, Nat Protoc 2015). 2014, the generated cells have been applied for lung Cur- disease studies by other research groups. we are working on culture conditions that rently, can direct the early human lung cells towards The avail- either airway or distal alveolar cells. ability of each of such enriched cell population provides a valid platform for studying lung dis- eases originating in both airways and alveolar, such as severe influenza viral infection and lung cancer. STEM CELL AND REGENERATIVE MEDICINE REGENERATIVE AND CELL FOR STEM CENTER 60 • IMMPACT REPORT anyuan Zhang;Dong H. Kim;QilinCao. Human Jiaqian Wu;Yu- Georgene W.Hergenroeder; Xue; Liu; Ying Zheng;ShenglanLi;Haipeng Yiyan 2016 Nov15. Stroke. 2016Dec;47(12):3005-3013. Epub Aneurysm andSubarachnoidHemorrhage. 1) MutationinthePathogenesisofIntracranial bospondin Type 1DomainContainingProtein Nalbach, S.;DePalma, S;etal. THSD1 (Throm- Santiago-Sim, T.; Fang, X.; Hennessy, M.; KEY PUBLICATIONS •Clinical trials. •Genetic aneurysmresearch. •Stem celltherapyforspinalcordinjury. RESEARCH PROJECTS and MemorialSloanKetteringCancerCenter. versity MedicalCollege, The New York Hospital, the Dana-FarberCancerInstitute, CornellUni- Medical School, Brighamand Women’s Hospital, coming to Texas, IheldpositionsatHarvard at Harvard, thenneurosurgeryatUCSF. Priorto Medicine, Icompletedgeneralsurgerytraining of California, SanFrancisco(UCSF)Schoolof Stroke Association. National InstitutesofHealthandthe American geons. Iamtherecipientofgrantsfrom Report’s Top 1%Doctors, and America’s Top Sur- and spinalcord. neural stemcellsforimplantationintothebrain in familialpatients. We alsoworktodevelop defect proventocauseintracranialaneurysms Our grouprecentlyidentifiedthefirstgene velopment, andtreatmentofbrainaneurysms. faculty andresidents/fellows. System. Currently, thisgroupincludesover100 fortheMemorialHermannHealthcare efforts tute (MNI), Ialsoleadtheclinicalneuroscience As directoroftheMischerNeuroscienceInsti- of NeurosurgeryatMcGovernMedicalSchool. CENTER FORSTEMCELL AND REGENERATIVE MEDICINE A graduateofStanfordandtheUniversity and I wasnamedtotheUSNews World My researchhasfocusedontheorigin, de- I amprofessorandchairoftheDepartment human neuralstemcellsinchroniccervicaland ing safetyofintramedullarytransplantation Hsieh, J.;Huhn, S.;Curt, A.; Guzman, R. Emerg- Casha, S.;Fehlings, M.; Anderson, K.D.; Gage, A.; Kurpad, S.;Parr, A.; Ganju, A.; Aarabi, B.;Kim, D.; Levi, A.D.; Okonkwo, D.; Park, P.; Jenkins, A.; 20;7:41008. spinal cordinjury. 2017Jan ScientificReports. in thesub-chronicandchronicstagesof analysis ofcodingandlongnon-codingRNAs R.; Kim, D.H.; Cao, Q.; Wu, J.Q. The systematic Duran, R.C.; Yan, H.;Zheng, Y.; Huang, X.;Grill, 2017 Jan5;19:55-64. iPSCs forSCItherapy. 2016;StemCellRes. neural progenitorsderivedfromintegration-free Variants. Identification ofthe THSD1R450XMutationin LargeFamilywithIAandtheSpectrum of THSD1Rare Advancing thefieldofneuroscience Clive andNancyRunnelsChairinNeurosurgery Memorial Hermann–TMC Director, MischerNeuroscienceInstitute Professor andChair, L.Vivian ofNeurosurgery SmithDepartment Dong Kim, MD Clinical Trials Nurse:RebeccaMartinez KristaQualmann Genetic Counselor: Yuanqing YanProfessor: Assitant Zhen Xu YanningRui; Professor: Research Assistant LAB MEMBERS May 2017. thoracic spinalcordinjury. Neurosurgery. 24 IMMPACT REPORT • • • • 61 KEY PUBLICATIONS H.; Mishra, Wei, S.P.; Tarnawsky, M.; Kobayashi, B.; Davis, P.; Wenzel, N.; Azevedo Portilho, A.; Hemogenic M. Yoshimoto, B.; Hadland, J.; Wu, to Hematopoiet- Transition Endothelial Cells Can Lymphocyte-Biased ic Stem Cells through a B-1 State during Maturation in the Mouse Embryo. 2019. 13 (1): 21-30, Stem Cell Reports. N.; Azevedo Portilho, M.; Kobayashi, Y.; Lin, B.; Davis, P.; Wenzel, Y.; H.; Liu, Gao, A.; Mishra, Engraft- Long-Term M. Yoshimoto, M.C.; Yoder, ment of ESC-Derived B-1 Progenitor Cells Sup- Stem ports HSC-Independent Lymphopoiesis. 2019. 12(3):572-583, Cell Reports. B-1 progenitor acute lymphoid M. Yoshimoto, 2019. Blood. 133(24):2557-2558, leukemia. LAB MEMBERS Assistant professor: MD, Michihiro Kobayashi PhD Samuel Research assistants: Chika Nishida MD, Valiente Noemi Cornelius, A. tion in the mouse embryo utilizing single-cell RNA-sequencing. B-1 biased progenitor differentiation from the hemogenic endothelial cells in the mouse embryo. mechanisms for maintaining B-1a cell self- renewal ability. HSC-dependent B-1 cell development from embryos to adults. Knowledge obtained from these projects will Knowledge obtained from these Development cells and innate-like hematopoietic stem of embryo B cells in the mouse Momoko Yoshimoto, MD, PhD MD, Yoshimoto, Momoko Associate Professor •Identify important- molecules for HSC matura A lineage tracing mouse model was injected into day 9 pregnant mother and cdh5+ Tamoxifen embryos. Cdh5CreERT2: Rosa-Tomato on the following day. Tomato+ endothelial cells were labeled with •Understanding the divergent point of HSC and •Elucidating cell-intrinsic and cell-extrinsic fate decision and maturation. where HSCs are help us to improve the system which may in vitro, produced from human iPSCs the patients with be utilized for cell therapy to leukemias. hematological disorders and RESEARCH PROJECTS •Lineage tracing for HSC-independent and/or The hematopoietic stem cells (HSCs) that B-1 cells are unique murine innate immune B-1 biased progenitors and precursor of HSCs produce all types of blood cells in the body are first generated in the aortic region of the mouse embryo at embryonic day (E) 10-11. waves there are multiple Interestingly though, of blood cell production prior to the emergence of the first HSC from endothelial cells (referred to as hemogenic endothelial cells: HECs) and T-, these blood cells include erythro-myeloid, recently found have We and B- lymphoid cells. that innate-like B-1 lymphocytes and the first HSCs are produced simultaneously from HECs. are elucidating 1) what molecular signals We determine the divergent point between innate- 2) how like B-1a biased and multi-potent HSCs, embryo-derived B-1 progenitors contribute to 3) how and postnatal peritoneal B-1 cell pool, HSC-precursors mature into adult-repopulating HSCs in a limited time window of embryonic development. cells that are distinguished from conventional localize in B-1 cells adoptive B cells (B-2 cells). the peritoneal and pleural cavities and secrete display- T cell help, natural antibodies without ing important roles in the first line of defense atherosclerosis, against various infections, It has been postulated for and autoimmunity. decades that B-1 cells are derived from fetal not from adult bone marrow progenitor cells, based on the results of transplantation HSCs, Our aim is to identify the main source assays. of HSC-independent B-1 progenitor cells and evaluate its real contribution to postnatal B-1 utilizing various lineage tracing mouse cell pool, models. are produced from hemogenic endothelial However, cells simultaneously in the embryo. it is still unknown what molecules determine the cell fate of hemogenic endothelial cells By utilizing into these two types of progenitors. lineage tracing mouse transplantation assays, we and single-cell RNA-sequencing, models, are elucidating the biological and molecular mechanisms that are responsible for this cell STEM CELL AND REGENERATIVE MEDICINE REGENERATIVE AND CELL FOR STEM CENTER 62 • IMMPACT REPORT CENTER FORSTEMCELL AND REGENERATIVE MEDICINE continue applyingpatient-specific iPSCsand date uniquegenefunction intumoretiology. We therefore providesa powerful systemtoeluci- alteration. The patient-specificiPSCmodel osteosarcoma mustbeduetothesinglegene fibroblasts, anyrecapitulatedfeaturesof iPSCs weregeneratedfromnon-transformed mediated diseasepathogenesis. Sincethese a dish” platformforelucidatingp53mutation established LFSdiseasemodelisa “disease in and tumorigenicability, suggestingthatour including defectiveosteoblasticdifferentiation osteoblasts recapitulateosteosarcomafeatures et al, Trends Cancer2016). LFSiPSC-derived osteosarcoma (Lee, etal, Cell2015;Gingold, logical mechanismscausedbymutantp53in patient-specific iPSCstodelineatethepatho- Fraumeni syndromediseasemodelbyusingLFS ESCs. We haveestablishedthefirsthumanLi- patient-specific iPSCsand/orengineered cancer pathologicalmechanismsbyapplying transplantation-based therapies. ing, personalizedhealthcare, cell andeventually discovery anddevelopment, screen- toxicology to elucidatediseasepathogenesisfordrug generate differentiatedcellsthatcanbeused a powerfulandunlimitedsourceofcellsto like embryonicstem(ES)cells, iPSCsprovide ferentiate intoallcelllineagesofanorganism indefinitelyand dif- their abilitytoself-renew Shinya Yamanaka in2006. Characterizedby byDr.cell (iPSC)methodologiesdeveloped become feasiblewithinducedpluripotentstem perfect modelsystemtostudyosteosarcoma. osteosarcoma development, whichprovidesa suppressor gene, haveincreasedincidenceof caused bygermlinemutationsinthep53tumor inherited autosomaldominantcancerdisorder with Li-Fraumenisyndrome(LFS), agenetically with osteosarcomadevelopment. Patients and RB1deletion)arestronglyassociated children. Geneticalterations(e.g., p53mutation among leading causeofcancermortality Our researchisdedicatedtounderstanding Modeling humangeneticdiseasehasrecently After leukemia, osteosarcomaisthesecond Familial cancersyndromesinadish Assistant Professor Dung-Fang Lee, PhD of TP53, drives cancerthroughvarioushallmarks. which further andprogression.development Eachcolor-coded nodeindicatesgain-of-function ofspecificmutation weapons(downstreamtargetsindicted inthefigure)todrivecancer protein armp53with new Mutant p53gain-of-functiondrivercancer throughcancerhallmarks. Differentmutations onp53 38(10):908-927, 2017. targeting oncogenicp53. Trends PharmacolSci. precisioncancertherapy platform todevelop Li-Fraumeni syndromediseasemodel: A C. Strong;RuiyingZhao;Dung-FangLee. Ruoji Zhou; An Xu A; JulianGingold; Louise KEY PUBLICATIONS •Model familialcancersyndromewithpredis- •Systematic analysesofgenomealterations analysesandcharacterization •Systems-level RESEARCH PROJECTS illuminate cancerpathologicalmechanisms. TALEN/CRISPR geneticallyengineeredhESCsto iPSC approaches. position toosteosarcomabypatient-specific ment. - during LFS-associatedosteosarcomadevelop coma. of mutantp53inLFS-associatedosteosar- Technicians: Ying Liu Technicians: Ying Students: BrittanyEJewell Zhu Post-doctoral fellows: An Xu, MoLiu, Dandan LAB MEMBERS Cell Rep.6;28(6):1400-1409.e4 2019Aug inembryonic stemcells.safeguards self-renewal Lemischka; Dung-FangLee. Genomicintegrity Christoph Schaniel;Kateri A. Moore;Ihor R. Lin; HaidanLuo;Huiling Yang; RuiyingZhao; Zhou; Yu Ruoji Gingold; Yen-SinJian Tu; Ang; Jie Su;DandanZhu;ZijunHuo;Julian A. Nov 20:115(47):E11128-E11137. mechanism. ProcNatl Acad SciUS A. 2018 viaautocrineandparacrine development role ofSFRP2inp53-mutantosteosarcoma R Lemischka;ChristophSchaniel. Oncogenic Jun Zhu;Kateri A. Moore;Dung-FangLee;Ihor Michael GDaniel;JieSu;ElizabethG. Demicco; M.Jeffrey Bernitz; Ye Yuan; Andreia MGomes; Huensuk Kim;Seungyeul Yoo; RuojiZhou; An Xu; IMMPACT REPORT • • • • 63 8, 2017. Article ID 9182748, https://doi. Article ID 9182748, 2017. 8, [Epub ahead org/10.1155/2017/9182748 of print and Liu, D.; Yang, H.; Xue, D.; S.; Li, Li, D.; Jia, TCGA database for genes of Mining (2018). Y., prognostic value in glioblastoma microenviron- doi: Apr 16. 2018 Aging (Albany NY). ment. of [Epub ahead 10.18632/aging/101415. print] PubMed PMID: 29676997 LAB MEMBERS Research scientist: Shenglan Li Research associate: Haipeng Xue 15 September 2017. 15 September 2017. PMID:28073086 (2017) Y. Liu, D.; H.; Li, A.; Xue, Zhang, S.; Li, One-step piggyBac transposon-based genes. CRISPR/Cas9 activation of multiple Mol Ther Nucleic Acids. 8:64–76, doi. http://dx.doi.org/10.1016/j. doi. 8:64–76, PMID: 28918057 omtn.2017.06.007. PMCID:PMC5485764 H.; D. L.; Kim, H.; Sun, S.; Xue, B.; Li, Long, Effects of propofol treatment in (2017). Y. Liu, neural progenitors derived from human-induced Oct Plasticity. pluripotent stem cells. Neural Rapid generation of astrocytes from human iPSCs by endogenous activation of astrocyte lineage cell line was Human iPSCs specific transcription factors with the piggyBac-CRISPR activation system. transcrip- transfected with all-in-one vectors expressing guide RNAs that activate SOX9-NFIA-NFIB-NFIX nearly all cells expressed astrocyte markers S100B (A), Fourteen days post transfection, tion factors. Nuclei are revealed by (E). A2B5 while did not express glial progenitor marker GFAP (B) and CD44 (F), (D) and (H) are overlapped images. G). (C, DAPI A Neurogenin 2 knockin human iPSC reporter cell line made using the CRISPR/Cas9 system. A Neurogenin 2 knockin human iPSC reporter cell line made using the CRISPR/Cas9 system. NEUROG2-mCherry human iPSC clones are induced as embryoid bodies (EBs) which glow red under the native NEUROG2 antibody staining (green) confirms that mCherry (red, fluorescence microscope (A). signal) expression faithfully reflects the endogenous NEUROG2 expression along the differentiation C). pathway (B, Human pluripotent stem cells in cell-based therapy for CNS in cell-based stem cells Human pluripotent diseases Ying Liu, MD, PhD MD, Ying Liu, Assistant Professor We have been pursuing basic and translation- We Human induced pluripotent stem cells (iPSCs) iPSCs. progenitors for cell-based therapy in spinal cord injury . patient derived iPSCs and neural populations tory networks in glioblastoma. al research in the following two areas: (i) stem and (ii) cell biology and regenerative medicine, pathogenesis of neurodegenerative disease and focus on dissecting the neural We CNS injury. developmental pathways and the corresponding Our long- pathogenesis in spinal cord injury. term goal is to identify therapeutic targets for the treatment of CNS diseases. provide autologous materials for patients, which theoretically omit the need for immune the more clini- have optimized We suppression. integration-free hiPSC generation cally relevant, protocol and performed directed differentiation of patient-specific iPSCs into neural stem cells, as ma- as well neuronal and glial progenitors, transplan- ture cell types for disease modeling, repair, neural regeneration and tation studies, The highly ef- and drug screening and testing. ficient CRISPR gene editing tool adapted in the lab allows for quick creation of neural lineage reporters and multigene activation for lineage These neural lineage specific cells are induction. applied to in-depth study of signal transduction in disease and development. RESEARCH PROJECTS integration-free •Generation of patient-specific, •Identification of optimal neural lineage •Down syndrome disease modeling using •Molecular changes in gene expression regula- KEY PUBLICATIONS K.; H.; Schmitt, S.; Xue, Li, Y.; Zheng, Y.*; Liu, D.H.; Kim, Y.; J.; Zhang, Wu, G.W.; Hergenroeder, (2017) Human neural progenitors Q*. Cao, derived from integration-free iPSCs for SCI Stem Cell Res. 2017 Jan 5;19:55- therapy. [Epub doi: 10.1016/j.scr.2017.01.004. 64. ahead of print] (*corresponding authors) STEM CELL AND REGENERATIVE MEDICINE REGENERATIVE AND CELL FOR STEM CENTER 64 • IMMPACT REPORT microenvironment is underway. of quiescentcellsand theirinteractionwith their survivalinbone marrow. Characterization to understandthemolecularmechanisms of and increasedtumorformation, itisimportant ment andpotentiallyleadtodrugresistance cells canescapethechemotherapeutictreat - and causesosteolyticlesions. Sincequiescent nancy thatproliferatesprimarilyinbonemarrow microenvironment. MMis aplasmacellmalig- and theirinteractionwiththebonemarrow roles ofthequiescentmultiplemyeloma(MM) applications. in cancercellswillhavedirecttranslational pounds thattargetdrugresistancepopulations cells arehighlydrugresistant, discovery ofcom- of PAX5 silencedcells. GiventhatPAX5 silenced select compoundstargetthesurvivalpathways and prestwicklibraries. We discoveredthat compounds ofNCIoncology, customclinical, screening usinglibrariescomprisedof3,991 the bonemarrow. silencing ledtoincreasedcancercellsurvivalin potential tumorsuppressor. Moreover, PAX5 in xenograftmice, indicatingthatPAX5 isa lymphoma leadstoincreasedtumorformation discovered thatPAX5 silencinginmantlecell nant ofnormalBcelllineagedevelopment. We those factorsispairedbox5(PAX5), adetermi- with bonemarrowmicroenvironment. Oneof lignant Bcellsanddelineatingtheirinteraction selective growthandsurvivaladvantagestoma- to deciphermolecularpathwaysthatconfer chemotherapeutic agents. for dormantclones, whichareoftenresistantto bone marrownichesprovidea “hiding place” tion fromchemotherapy-inducedapoptosis. The multiple myelomacellgrowthaswellprotec- niche, whichprovidesanenvironmentfor malignant cellsandtheirlocalbonemarrow also requirescomplexrelationshipsbetween dependent ontheirgenomicabnormalities, but CENTER FORSTEMCELL AND REGENERATIVE MEDICINE We arealsoconductingresearchdelineating We haveconductedhighthroughputdrug The majorgoalsofmyresearchprogramare The behaviorofcancercellsisnotonly sayed fortheappearance ofautophagosomesusingaconfocal microscopy. flux processes.TRIM44 increasesautophagy TRIM44expressionwasmodified incancercellsandas- the bonemicroenvironment Deciphering mechanismsofhumancancercellsurvivalwithin Annie andBobGrahamDistinguishedChairinStemCellBiology Associate Professor Nami McCarty, PhD • Proteinhomeostasisisorchestratedby ofsmallmoleculeinhibitors •Development •Survival mechanismsofdormantmultiple RESEARCH PROJECTS control incancerprogression. delineating functionsofproteinhomeostasis to normalcellularfunctions. We focuseson disruptions toproteinhomeostasisbutalso protein misfolding, whichcanleadtonotonly protein assemblyormodificationpromotes transport, anddegradation. Inappropriate coordinated proteinsynthesis, folding, test theirefficaciesinthepatients. models forpre-clinicalstudiesandplanto andtestthesecompounds inanimal develop drugresistance.that develop We willfurther selectively targetmantlecelllymphomacells screening toidentifythecompoundsthat have conductedhighthroughputchemical to targetdrug-resistantlymphomas: We chemotherapies. cells evade delineate howdormantmultiplemyeloma with bonemarrowmicroenvironmentto genes inthemultiplemyelomainteraction continue tocharacterizefunctionsofthese different nichesofthebonemarrow. We will quiescent multiplemyelomacellsfromthe ray analysestoidentifygenesexpressedin the bonemarrow: We conductedmicroar- myeloma cellsandtheirmicroenvironmentin Research assistants:JiacuiChen Post-doctoral fellow:LynLiu, PhD LAB MEMBERS 33:469-486. PMID:30089913 via deubiquitinationfornichecontrol. Leukemia escent multiplemyelomacellsstabilizesHIF-1a McNiece, I.;McCarty, N. (2019) TRIM44 inqui- Chen, Z.;Lin, T-C.; Bi, X.;Lu, G.;Dawson, B.C.; 30647863 Oncotarget editorial9:37276-37277. PMID: tumor eradication, istoogoodtobetrue? McCarty, N. (2018)Battlingquiescencefor Blood” asanEditor’s pick. 2017. wasfeaturedin This article “this weekin dispersal duringhypoxia. Blood130:763-776. coordinates mantlecelllymphomasurvivaland L.J.; andMcCarty, N. BifurcatedBACH2control Zhang, H.;Chen, Z.;Miranda, R.N.;Medeiros, 13:627-628, 2017. regulatorynetwork.IL6-autophagy Autophagy cancer chemoresistancebytargetingthe TGM2- Zhang, H.;andMcCarty, N. Tampering with KEY PUBLICATIONS IMMPACT REPORT • • • • 65 sis from the hPSC-derived chondroprogenitors sis from the hPSC-derived chondroprogenitors rise to articularand joint progenitors to give chondrocytes. hyaline the molecular basis of permanent, cartilage formation from the hPSC-derived joint progenitor-like cells. hPSC-derived chondroprogenitors and joint progenitor-like cells in immunocompromised animal models. RESEARCH PROJECTS •Further the process of chondrogene- defining to elucidate •Comparative omics analyses •Joint articular cartilage repair with KEY PUBLICATIONS N.; Zhao, Q.; Matthias, Yan, H.; K.; Oda, Umeda, “Long-term (2015) B.R.; Nakayama N. J.; Davis, expandable SOX9+ chondrogenic ectomes- enchymal cells from human pluripotent stem 4:712-26. Stem Cell Reports, cells” S.; Nakayama, Beckman, Y.; Tang, A.; H.; Lu, Li, (2016) J. M.; and Huard, M.; Hogan, N.; Poddar, “The Superior Regenerative Potential of Muscle Articular Cartilage Repair Derived Stem Cells for and Chondro- Attributed to High Cell Survival is Dev., Methods Clin. Ther. Mol. genic potential” 3:16065. B.K.; Ang, A.; N.; Pothiawala, Matthias, J.Y.; Lee, I.; S.; Martin, Pigeot, D.; J.; Sun, M.; Li, Lee, (2018) N. and Nakayama, Y.; J.; Huang, Huard, “Pre-transplantational control of the post- transplantational fate of human pluripotent Stem Cell Reports, stem cell-derived cartilage” 11:440-53. LAB MEMBERS Sahbazoglu Research assistant: Berke E. Senior research associate and animal special- ist: Nadine Matthias Transient cartilage from standard chondropro- Transient and permanent cartilage from joint genitors (1), progenitor-like cells (2) recovered from NSG mice after 8 weeks. Large quantity of articular cartilage-forming establish methods to generate permanent establish methods to generate cartilage as unmineralized cartilage that stays we aim to for a long time after transplantation, achieve the following two goals; 1) generating and from hPSCs, the embryonic joint progenitor 2) demonstrating that they allow the culture- made cartilage to be stably maintained even af- and that they show superior ter transplantation, capacity of articular cartilage to currently repair previouslyWe discovered a way available cells. extent, and to a limited to selectively generate, expand joint progenitor-like cells from hPSCs. purify and further characterize the joint To hiPSC we have generated progenitor-like cells, lines that carry fluorescence marker genes in Further- the joint progenitor marker gene loci. that cartilage we have recently discovered more, made with the joint progenitor-like cells is in fact maintained as unmineralized cartilage we have determined that In addition, in mice. controlling cAMP signaling leads to cartilage displaying very limited bone forming capacity pseudo-permanent after transplantation (i.e. cartilage) even from the chondroprogenitors. both on the we are currently focusing Therefore, characterization of the joint progenitor-like cells to elucidate molecular basis of their permanent and on the elucida- cartilage-forming capacity, tion of signaling mechanisms required for the expect We formation of permanent cartilage. that such mechanistic studies may lead to a proper method to make clinically relevant adult stem cells more suitable for joint cartilage regeneration. cells; long-term expansion of PSC-derived Rapid loss of human chondroprogenitors. chondrogenic activity of adult stem cells during expansion culture is still a problem to be solved for application of them to cartilage regenera- previouslyWe established culture tive therapy. conditions that maintained and expanded the hPSC-derived chondroprogenitors for an without loss of their extended period of time, Such stable expan- cartilage-forming capacity. sion of chondrogenic activity is currently hard to are interested We achieve with adult stem cells. in elucidating the mechanistic basis of such which may be applied to improve the capacity, expansion culture method for adult stem cells in the future. Pluripotent stem cell biologyPluripotent stem joint morphogenesis and Synovial Naoki Nakayama, PhD Naoki Nakayama, Associate Professor in Stem Cell BiologyGraham Distinguished Chair Annie & Bob Synovial joint is composed of articular carti- What is the molecular basis of human ligament and synovial lage (meniscal cartilage), membrane and is formed during embryogenesis Injured from a multipotential joint progenitor. joint cartilage is not spontaneously repaired There has leading to osteoarthritis. in humans, been considerable interest in the clinical ap- plication of stem cells to the repair of damaged current cell therapies using cartilage; however, expanded articular chondrocytes and adult stromal cells such as mesenchymal stem cells, face the problems of low yield of cells and their tendency to yield unstable cartilage that is later A transient cartilage, degraded or mineralized. in the is typically found destined to form bone, joint cartilage is a per- In contrast, growth plate. manent cartilage- generated from joint progeni tor cells distinct from those for generating the we hypothesize Therefore, growth plate cartilage. that the embryonic joint progenitor would be the best cell-type for the regeneration of joint allow ligament regen- which may also cartilage, whether Pluripotent stem cells (PSCs), eration. or induced from adult derived from an embryo, are expected to differentiate into any cells, cell-types of the human body through processes making human (h) that mimic embryogenesis, PSCs a promising source of embryonic cells for we have been Therefore, regenerative medicine. investigating the developmental process from human and mouse (m) PSCs to joint progenitor cells. stem/progenitor cells to form permanent have previouslycartilage? We developed and progeny representing the purified from hPSCs, and three embryonic origins of chondrocytes, demonstrated that they are able to expand and differentiate into corresponding chondrocyte All such precursors (chondroprogenitors). chondroprogenitors are capable of giving rise most However, to hyaline cartilage in culture. of them are mineralized and turned into bone when transplanted into immunocompromised resembling growth-plate cartilage and mice, In order to adult stem cell-derived cartilage. STEM CELL AND REGENERATIVE MEDICINE REGENERATIVE AND CELL FOR STEM CENTER 66 • IMMPACT REPORT •Lymphatic flowasaregulatorofthespread •Effects offlowonhematopoieticstemcell RESEARCH PROJECTS options forpatientsaffectedbycancer. ment, treatment wehopeto identifynew approaches tostudythetumormicroenviron- primary tumor. Byapplicationofbioengineering ute tothesystemicspreadofcancerfrom activation ofoncogenicpathwaysthatcontrib- impact offluidforceoninvasivepotentialand the experienced bycancercellsandevaluate vasculature, wemodulatethefrictionalforce microchips designedtomodelthelymphatic cancer cellsspreadthroughoutthebody. Using forces mayplayinregulatinghowaggressively remains unclearwhatrolelymphaticorvascular also beenimplicatedintumorbiology, butit and transplantationassays. microfluidics, pharmacology, mousegenetics, stemcellfunction,tools toevaluate including stem cellpotential, andweemployvarious occurs inresponsetoflowthatpotentiates syndromes andleukemias. Complexsignaling and cancers, suchasbonemarrowfailure cells fortreatmentofhematologicdisorders to expandimprovedsourcesofthesestem might usethisinformationinthelaboratory development. We areinterestedinhowwe emergence ofbloodstemcellsduringembryo frictional forcecausedbybloodflowpromotes cell fateandbehavior. system andlymphinthelymphaticsimpacts generated bytheflowofbloodincirculatory CENTER FORSTEMCELL AND REGENERATIVE MEDICINE of cancer. fate. Fluid flowandhydrostaticpressurehave One ofourresearchprojectsaddresseshow Our labstudieshowbiomechanicalforce Associate Professor Pamela Wenzel,PhD through themicrochanneltomimiclymphaticflow. is treatedwithcollagenmatrix, followedbyintroductionofcancercells. Culturemediumispushed through thelymphaticvasculature. A microchannel embeddedinthecenterofmicrofluidicsdevice monitoring ofgeneactivityunderconditionsthatacancercellmayexperienceduringmetastasis We engineerbiomimeticmicrochipsthatpermitreal-timevisualizationofcancercellmigrationand Effects offlowonstemcellpotentialandcancermetastasis the cellcycle. CellCycle.17(2):147-153, 2018. TAZ respondstofluidshearstressregulate Lee, H.J.;Ewere, A.; Diaz, M.F.; and Wenzel, P.L. munications. 8:14122, 2017. to promotecancercellmotility. NatureCom- Wenzel, P.L. Fluidshearstressactivates YAP1 Zhang, S.;Sevick-Muraca, E.M.;Hagan, J.P.; and Lee, H.J.;Diaz, M.F.; Price, K.M.;Ozuna, J.A.; KEY PUBLICATIONS reduction incancercellmotilitybytreatment with YTIP underfluidflow. that interrupts YAP1 function, aproto-oncogene, inthecancercells. Asterisks representasignificant creased movement, buttheincreasedmigrationcanbeblocked bytreatmentwithasmallpeptide YTIP site tosecondarymetastaticsitesinthebody. The shapeofthecellchangestoaccommodatein- cancercellmotility,Flow elevates formovementofcellsfromtheprimarytumor aprocessimportant Senior researchassociate:MiguelDiaz Sandeep Dumbali Post-doctoral fellows: Amina Mohammadalipour, Graduate student:PaulinaHorton LAB MEMBERS 583, 2019. lymphopoiesis. 12(3):572- StemCellReports. hematopoieticstemcell-independent supports embryonic stemcell-derivedB-1progenitors and Yoshimoto, M. Long-termengraftmentof G.; Liu, Y.; Wenzel, P.; Davis, B.; Yoder, M.C.; Lin, Y.; Kobayashi, M.;Mishra, A.; Hongyu, IMMPACT REPORT • • • • 67 tory RNAs; and modulate key regulators to differentiation steer the direction of stem cell and improve efficiency/safety. cord injury and therapeutic targets for spinal neurological diseases. Characterize molecular signatures and identify •Characterize molecular signatures KEY PUBLICATIONS J. J. J.; Mao, M.;Wu, J.; Chen, L.; Zhou, He, Tissue Regeneration Parenchymal and Stromal Organ by Pivotal Signals Reinstated in Tooth of 2019 Nature Materials. Decellularized Matrix. doi: 10.1038/s41563-019- Jun;18(6):627-637. PMID:31114073 0368-6. H.; Zheng, Y.; C. Wang, R.; Cuevas-Diaz Duran, Brain region-specific Q. J. Wu, B.; and Deneen, gene signatures revealed by distinct astrocyte subpopulations unveil links to glioma and (2019); eNeuro neurodegenerative diseases. PMID:30957015 10.1523/ENEURO.0288-18. Long non-coding RNAs: important regulators in Applied Neuropathology and CNS and disorders. doi: 10.1111/ 2019 Jan 13, Neurobiology. PMID: 30636336. nan.12541. LAB MEMBERS PhD; Xizi Wei., Post-doctoral fellows: Haichao PhD MS; Xu Li, MD, Wu, Prajapati Tanuj Undergraduate student: systems-based approaches involving genom- and functional assays to bioinformatics, ics, investigate gene expression and regulatory mechanisms during stem cell differentiation; pinpoint key transcription factors and regula- valuable data source and a powerful analysis valuable data source and a framework of cod- for functional investigations in CNS cell types ing and long non-coding RNAs work has been recognized with Wu’s Dr. and SCI. including the prestigious honors and awards, Kirschstein Ruth L. National Institutes of Health Individual Award for National Research Service and the International Postdoctoral Fellows, Annual Society for Stem Cell Research (ISSCR) the National Institute of Award, Travel Meeting Award Health Pathway to Independence (PI) Lloyd and B.A. R01 and the Senator (K99/R00), A reviewer for NIH, Award. Bentsen Investigator State Department of Health-Spinal York New and ANR, MRC, Cord Injury Research Board, Wu has presented talks and Dr. many journals, lectures at national and international confer- She has developed a ences and institutions. and wrote many authored two books, patent, PNAS, articles that have appeared in Nature, Plos Genetics, of Neuroscience, the Journal Scientific Reports, and , Genome Research among others. RESEARCH PROJECTS •Wu laboratory combines stem cell biology and Gene transcription and regulation of stem cell differentiation cell differentiation of stem and regulation Gene transcription and neural injuries Jiaqian Wu, PhD Jiaqian Wu, Associate Professor Dr. Jiaqian Wu is an associate professor with Wu is an associate professor Jiaqian Dr. Wu Lab uses interdisciplinary approaches including molecular biology, genetics, genomics, proteomics, and bioinformatics to study gene expression and and bioinformatics proteomics, genomics, genetics, Wu Lab uses interdisciplinary approaches including molecular biology, transcriptional regulation in stem cells and the nervous system. STEM CELL AND REGENERATIVE MEDICINE REGENERATIVE AND CELL FOR STEM CENTER Smith Department of Vivian L. tenure in the Neurosurgery and Center for Stem Cell and Wu led the NIH Dr. Regenerative Medicine. Mammalian Gene Collection effort and cloned thousands of mammalian genes which are publicly available through GE Dharmacon now. ENCODE Wu was also closely involved in the Dr. and she employed interdisciplinary project, - transcrip approaches to study gene expression, networks and regulatory tion factor regulation, In of stem cell self-renewal and differentiation. Wu has carried Dr. her independent laboratory, out unprecedented transcriptome profiling of and vascular glia, eight highly purified neuron, Wu lab identi- The cells from brain by RNA-Seq. fied a large number of novel long non-coding and they identified the role of lncRNA in RNAs, oligodendrocyte precursor cell (OPC) formation for the first time using functional and genetic diseases One of the neurological experiments. injury Wu is focusing on is spinal cord that Dr. Wu lab has already published studies The (SCI). for acute and chronic SCI phases in mouse and Wu lab provided The rat contusive injury models. 68 • IMMPACT REPORT T synthetic small moleculesthatmodulatethe discovery ofbiologics,naturalproducts, and that have criticalroles in humandiseases;2) 1) signalingmechanismsof receptors andenzymes Current research activitiesat include: TTI-IMM development. cancer antibodydrug cancer biology, fungalnaturalproducts, and significant scientificdiscoveries inthe areas of ofDefense,the Department andhave made Prevention andResearch Institute of Texas, and the National Institutes ofHealth, theCancer and thebiotechnologyindustry, suchasMerck, significant fundingfrom thepharmaceutical therapeutics. and establishmentofproof-of-principle for targets, identification and validation ofdrug Research conductedatthecenter focusesonthe therapeutic agentsanddiagnostictools. development, andcommercialization of Science CenteratHouston forthediscovery, System, andThe University of Texas Health Technology Fund, The University of Texas in 2010withfundingfrom the Texas Emerging TEXAS THERAPEUTICS INSTITUTE TEXAS THERAPEUTICS TTI-IMM investigators haveTTI-IMM brought in Medicine wasestablished (TTI-IMM) Foundation Institute ofMolecular exas Therapeutics Institute atThe Brown Chemistry A. Robert Welch Distinguished University Chairin Professor &Center Director Zhiqiang An, PhD School andUTHealth. discovery engine ofMcGoverndrug Medical Texas Therapeutics Institute is recognized asthe potential milestonepayments,androyalties. The deals resulted insignificantupfront payments, development. These licensing companies fordrug inventions haveTTI beenlicensedtobiotech induced liver injury, andviralinfections.Five diseases, spinalcord injury, fibrosis, acutedrug cancer, metabolicdiseases,neurodegenerative discoverythan 30active projects drug targeting institutions across Texas andthenationwithmore has establishedanetwork ofcollaborators from and development. During thelastnineyears, TTI monoclonal antibodyleaddiscovery optimization discovery platformfocusingonthetherapeutic research programs, hasbuiltamajordrug TTI to viralinfectionsandexperimentalvaccines. antibodies from animalsandhumansinresponse discovery; and3)characterizationof for drug activity ofthesetargetsaspotentialleadmolecules In additiontothebasicandtranslational IMMPACT REPORT • • • • 69 Partial leptin reduction as an effective In the context novel weight loss strategy. partial leptin reduction re- of obesity, stores hypothalamic leptin sensitivity and increased leads to reduced food intake, improved insulin and energy expenditure, strategies aimed at Thus, sensitivity. partially reducing circulating leptin may represent a promising approach for the treatment of obesity and diabetes Cell Metabolism doi. 2019. (Zhao et al., org/10.1016/j.cmet.2019.08.005). Multiple mechanisms of a LILRB4 neu- tralizing antibody contribute to anti-AML Mechanistic studies revealed activity. four concordant modes of action for the anti-AML activity of a LILRB4 neutralizing T cell suppres- antibody: 1) reversal of AML cell sion; 2) inhibition of monocytic tissue infiltration; 3) antibody-dependent cellular cytotoxicity (ADCC); and 4) an- tibody dependent cellular phagocytosis targeting LILRB4 with Therefore, (ADCP). antibody represents a new therapeutic AML strategy for treating monocytic Cancer Immunology 2019. (Gui et al., doi: 10.1158/2326-6066. Research CIR-19-0036.). Hui Deng; Jia Sun; Yingfeng Deng; Min Kim; Hui Deng; Jia Sun; Tiemin Liu; Lee; Ruth Gordillo; Charlotte E. Childs; Ningyan Zhang; V. Odle; Gwen Angela K. Kevin Elmquist; Kusminski; Joel K. Christine M. Scherer. Philipp E. An; and Williams; Zhiqiang W Partial Leptin Reduction as an Effective 2019. Cell Metabolism doi. Loss Strategy. Weight Novel org/10.1016/j.cmet.2019.08.005. LAB MEMBERS Leike Post-doctoral fellows: Zhiqiang Ku, Tan; Peng Zhao; Lingxiao Ye; (Simon) Li; Xiaohua Yuan Junquan (Jake) Liu; Zihao Graduate student: Hang Su Salazar T. Research coordinator: Georgina Xun Gui; Mi Deng; Hao Song; Yuanzhi Chen; Yuanzhi Xun Gui; Mi Deng; Hao Song; He; Fangfang Jingjing Xie; Zunling Li; Licai Huang; Yixiang Anami; Xu; Yasuaki Hai Yu; Xu; Xiaoying Yuan; Leike Li; Zihao Yu; Chenyi Yan Chai; Tao Huang; YiQihui Wang; Shi; Kyoji Charlene Liao; Ningshao Xia; Tsuchikama; X. Gao; Ningyan Zhang; Cheng Cheng George F. Disrupting 2019. An. Zhang; and Zhiqiang LILRB4/APOE interaction by an efficacious T cell suppression humanized antibody reverses Cancer Im- AML development. and blocks munology doi: 10.1158/2326-6066. Research CIR-19-0036. Schultz; Yi Robbie D. Zhu; Shangang Zhao; Alexandre Na Li; Zhenyan He; Zhuzhen Zhang; Xiong; Wei Caron; Qingzhang Zhu; Kai Sun; Discovery and development of therapeutic antibodies Zhiqiang An, An, PhD Zhiqiang Therapeutics Institute Texas Co-Director of the Professor and Chair in Chemistry Distinguished University Welch A. Robert Our group focuses on the discovery and Immune suppression is recognized nisms. and this notion is as a hallmark of cancer, largely based on studies on cellular immunity. Our recent studies have demonstrated a new of cancer suppression of mechanism immunity by impairment of antibody effector function mediated by proteolytic enzymes in the tumor microenvironment. Design of highly immunogenic vaccination. vaccines that induce neutralizing antibodies against a broad range of clinical isolates is one of the approaches in developing effective on-going project to have an We viral vaccine. aid the design of HCMV and dengue vaccines by profiling antibody response to the experi- mental vaccines in rhesus and humans. Our group has built a comprehen- discovery. sive antibody drug discovery platform with a focus on antibody lead optimization technolo- deep gies such as antibody phage display, sequencing of antibody encoding genes from affinity individual antibody expressing B cells, we Currently, and humanization. maturation, have multiple collaborative antibody drug discovery projects targeting various cancer types. development of therapeutic antibodies against we have three major Currently, human diseases. research areas. RESEARCH PROJECTS •Cancer antibody drug resistance mecha- •Antibodies response to viral infections and •Cancer therapeutic monoclonal antibody drug KEY PUBLICATIONS Freed; Zhiqiang Xun Gui; Daniel C. Ye; Xiaohua Xiong; Xuejun Wei Chen; Yuanzhi Ku; Leike Li; Ning- Wang; Fan; Xi He; Jian Liu; Hua Zhu; Dai 2019. An. Fu; Zhiqiang Tong-Ming yan Zhang; APMAP as a novel modulator Identification of 15(7): Plos Pathogens of HCMV infection. https://doi.org/10.1371/journal. e1007914. ppat.1007914. TEXAS THERAPEUTICS THERAPEUTICS TEXAS INSTITUTE 70 • IMMPACT REPORT new derivatives andoverproducedrug-precursor new synthesis of these naturalproducts tosupport organisms toaidinsupplying largequantitiesof and genomicmanipulationintheproducing potency. Inparallel, weusepathway genetics analogueswithincreased purity andnew strainswithimprovedproduct to producenew re-programmed pneumocandinbiosynthesis ecule for the antifungal drug CANCIDAS. We have including pneumocandinB0, mol- thestarting for thefamilyofechinocandinantifungaldrugs, characterized biosynthetic pathways responsible tion inhumandiseases. For example, wehave forpharmaceuticalinterven- families relevant model organisms, especially forbiosynthetic of microorganismsusingfilamentousfungias predict geneticallyencodedchemicaldiversity derivatives. new synthesisof these naturalproductstosupport organisms toaidinsupplyinglargequantitiesof and genomicmanipulationintheproducing cancers. Inparallel, weusepathwaygenetics useful ininterventioninfectiousdiseasesand bioactivechemistry harnessed togeneratenew novel biosyntheticmechanismsthatcanbe isms harborbiosyntheticgeneclustersand that naturalproduct-producingmicroorgan- products. We seektotestvarioushypotheses ing biosyntheticpathwaysofbioactivenatural medicinal chemistrysynthesis, andelucidat- products throughfermentationtosupport for therapeuticapplications, makingnatural involves testingmicrobialnaturalproducts lecular biology, andmicrobiology. Ourresearch sciences, organicchemistry, biochemistry, mo- diverse backgrounds, includingpharmaceutical members ofourlabandcollaboratorsfrom Institute ofMolecularMedicinebringstogether in the Texas Therapeutics Instituteandthe Multidisciplinary microbialbiomedicalresearch molecules forinventioninhumandisease. molecules continuetoyieldbreakthrough and geneticcapacityforsynthesisoforganic drugs.most important Their hyper-biodiversity INSTITUTE TEXAS THERAPEUTICS Our labemploysgenomicstointerpretand Microorganisms haveproducedmanyofour Kay and Ben Fortson DistinguishedChairinNeurodegenerativeDiseaseResearch Kay andBenFortson Professor Gerald F. Bills, PhD metabolites forinfectiousdiseasesandcancertherapies Genome mining, biosynthesis, anddiscoveryofmicrobial control); F.control); G.B. Arenicolin A;Arenicolin carcinoma), IMR-32(neuroblastoma) andBT-474 E. (ductal carcinoma)for: 5-fluorouracil (positive for humancelllines. D. Arenicolin B. E-G. Invitrotoxicityassayon cancercelllinesHCT-116 (colorectal the unusualacylated2-hydroxymethyl-4,5,6-trihydroxycyclohexenone responsibleforselectivecytoxicity Penicillium arenicolastrainNRRL8095from soilfromBritishColumbia, Canada. C. Arenicolin A, note Discovery ofthe Arenicolins, novelC-glycosylateddepsidesfromthefungusPenicillium arenicola. A-B. Development ofmethodsforreprogramming •Development •Biosynthesis ofnaturalproductsandpathway RESEARCH PROJECTS with otheracademicandindustriallaboratories. extracts areavailablethroughcollaborations to theactivity-causingnaturalproducts. These preparative HPLCandbioautography, guideus More refinedchromatographictechniques, e.g., our bioassaysagainstthetargetpathogens. fractions oftheextractsareidentifiedthrough such asflashorcolumnchromatography, active pathogens. After preliminarychromatography, directed atfindingmoleculesthataffecthuman biological effectsusinganensembleofassays foruseful of fermentedfungiareevaluated cus meningitisandcryptococcosis. Extracts coccus neoformans, ayeastcausingCryptococ- growth ofhumanpathogens, includingCrypto- bioactivenaturalproductsthatinhibit new molecules. useful fortreatinghumandiseases. to discoveroroverproducenaturalproducts transcription ofbiosyntheticgenesfungi engineering forimprovedantifungals. We alsocarryoutfundamentaldiscovery of Discovery of new antifungalsandother •Discovery ofnew Research assistant:Mr. Travis Roeder Perlatti Post-doctoral fellows:Dr. NanLan, Dr. Bruno LAB MEMBERS 20:3154-3167. Environmental Microbiology nocandin-producing fungusPezicularadicicola. a novelself-resistancemechanismintheechi- G.F. Bills. 2018. Genomics-driven discoveryof Yue, Q.; Y. Li;L. Chen;X. Zhang;X. Liu;Z. An; and 20:3325-3342. Microbiology of fungaltriterpenecyclases. Environmental fumafungin synthaserepresentsanovellineage Cox; Z. An; K. Yokoyama; andG.F. Bills. 2018. En- Kuhnert, E.; Y. Li;N. Lan;Q. Yue; L. Chen;R.J. Products 82:532–538. an undescribedNiessliasp. Journal ofNatural analoguesfrom Wortmannin andwortmannine Alspaugh; G.F. Bills;andJ.B. Gloer. 2019. Dischler, N.M,; L. Xu; Y. Li;C.B. Nichols;J.A. KEY PUBLICATIONS therapeutic agents. IMMPACT REPORT • • • • 71 KEY PUBLICATIONS KEY PUBLICATIONS L.; Liu, Wu, C.; Godoy, T.; S.; Chatterjee, Zhang, K.S.* GPR56 drives colorectal Q.J.; Carmon, drug resistance tumor growth and promotes expression via through upregulation of MDR1 Mol Cancer Res. a RhoA-mediated mechanism. 2019 [Epub ahead of print]. J.A.; S.C.; Simien, J.; Ghosh, Voss, A.; Azhdarinia, Q.; W.A.; Liu, Yu, J.; S.; Cui, Vargas, Hernandez Antibod- Anti-LGR5 K.S.* Evaluation of Carmon, Tumors ies by ImmunoPET for Imaging Colorectal Antibody-Drug Conjugates. and Development of 2018. Pharm. 15(6):2448-2454, Mol. A.; Thomas, L.; Wu, J.; Yi, X.; K.S.; Gong, Carmon, Marte- D.J.; Timson, I.; C.M.; Masuho, Moore, LGR5 receptor promotes K.A.; Liu Q.J. myanov, cell-cell adhesion in stem cells and colon J cancer cells via the IQGAP1-Rac1 pathway. 2017. 292(36):14989-15001, Biol Chem. LAB MEMBERS Research associate: Sheng Zhang Treena Chatterjee Students: Tressie Posey, Development of antibody-drug conjugates to target colon tumors and cancer stem cells. Investigation of the LGR5 function in cancer and drug resistance. metastasis, stem cells, Identification of novel therapeutic targets and associated signaling pathways in colon cancer. Schematic of an antibody-drug conjugate (ADC) and its mechanism of action in tumor cells. Experi- Schematic of an antibody-drug conjugate (ADC) and its mechanism of action in tumor cells. ADCs internalize within a colorectal tumor cell for drug release and (B) ments show (A) LGR5-targeted ADC treatment eliminates tumors in mice. Therapeutic strategies for targeting colorectal tumors and targeting colorectal strategies for Therapeutic cancer stem cells monometh- ADCs that incorporate the cytotoxin theyyl-auristatin E (MMAE) and showed could tumors in mice. destroy colon cancer cells and we are taking novel approaches to Currently, ADCs in modify and improve our LGR5-targeting number of tu- order to effectively treat a larger character- Our lab is also identifying and mors. ADC development. izing new targets for cancer group, Azhdarinia’s Ali In collaboration with Dr. we are using PET/CT imaging to select optimal therapeutic antibodies and evaluate them as diagnostics to stratify tumors which would Our therapy. ADC respond best to LGR5-targeted work will lead to the elucidation of the function and mechanism of LGR5 in CSCs and generate innovative therapeutic leads to target CSCs for the treatment and eradication of colon cancer. RESEARCH PROJECTS • • • Kendra S. Carmon, MS, PhD MS, Carmon, Kendra S. Assistant Professor Emerging evidence has shown that within Recent studies have established that LGR5 My current research is focused on investigat- TEXAS THERAPEUTICS THERAPEUTICS TEXAS INSTITUTE several malignant tumors types there different exists a subpopulation of cancer cells that These cells behave like normal stem cells. are referred to as cancer stem cells (CSCs) or tumor-initiating cells since they have the have been CSCs capacity to fuel tumor growth. and metastasis, implicated in drug resistance, for making them a major impediment relapse, it Therefore, the effective treatment of cancer. is essential to develop novel therapies that can ultimately target and destroy CSCs. G protein- (Leucine-rich repeat-containing, on a receptor expressed coupled Receptor 5), in is highly upregulated normal adult stem cells, colon Furthermore, primary colorectal tumors. CSCs which express LGR5 are capable of driving LGR5 In addition, tumor growth and metastasis. expression has been shown to be significantly elevatedseveral in other major tumor types, My and ovarian cancers. gastric, including liver, previous led to the discovery that LGR5 work functions as a receptor of secreted growth fac- to promote cancer cell called R-spondins, tors, adhesion and regulate cell signaling pathways involved in stem cell survival and tumor growth. These findings suggest that LGR5 plays an important role in cancer and could serve as a novel target for the development of innovative therapies which can eliminate CSCs. ing the function and cell signaling mechanisms of LGR5 in colon CSCs using colon cancer cell This lines and patient-derived tumor models. work will lead to identifying the role of LGR5 in and metastasis, the control of tumor growth, we are developing Furthermore, drug resistance. innovative therapeutics called antibody-drug conjugates (ADCs) that target and destroy similar to guided mis- colon tumors and CSCs, ADCs are comprised of a highly specific siles. monoclonal antibody attached to a cytotoxic that is only released once “warhead” chemical ADC binds and enters target tumor cells. the generated LGR5-targeted have successfully We 72 • IMMPACT REPORT of this family of important signalingmolecules.of thisfamilyimportant physiological functionsanddiseaserelevance and EPAC knockoutmousemodelstostudythe first-in-classEPACdeveloped selectiveinhibitors for thetreatmentofhumandiseases. We have be exploitedandcontrolledpharmaceutically signaling moleculessothattheirfunctionscan way specificmodulatorsfortheseimportant intricacies ofEPAC proteinsandtodesignpath- (EPAC). Ourgoalsaretounravelthesignaling exchange proteinsdirectlyactivatedbycAMP and functionofafamilycAMPsensors: chemical biology, tounderstandthestructure ics, and withpharmacology andcellbiology approaches, couplingbiochemistry, biophys- of humandiseases. We applymultidisciplinary jor stresssignalimplicatedinthedevelopment associated withsecondmessengercAMP, ama- INSTITUTE TEXAS THERAPEUTICS vehicle (Con). White linesoutlinetheareaofvaso-obliteration. (B, C)Graphsrepresentavascularandneovascuclarization areaatP17. tion. Representativeretinalvasculature (upperpanel)andhighmagnification images (lowerpanel)atP17inOIRmice treatedwithEpacinhibitorESI-09or Epac1 inpathological angiogenesisandasatherapeutictarget forretinopathy. OIR-inducedneovasculariza- (A)Pharmacological inhibitionofEpacprevents Our laboratorystudiesintracellularsignaling Walter andMaryMischerDistinguishedProfessorinMolecularMedicine Professor Xiaodong Cheng, PhD • •Examine therolesofEPAC proteinsinmajor •Structural andfunctionalanalysesofthe RESEARCH PROJECTS cardiovascular diseases. human diseasesincludingchronicpainand and inexploringtheirpotentialusesvarious isoform specificEPAC inhibitorsandagonists secondgeneration engaged indeveloping of fatalrickettsioses. Currently, weareactively EPAC andtreatment inhibitorsintheprevention Recently, wehaveidentifiedapotentialuseof cAMP -mediatedcellsignalinganddrugdiscovery bacteria Rickettsia. of microbialinfectionscausedbytick-borne candidates targetingEPAC forthetreatment ofnoveldrug Preclinical development cal inhibitors. knockout mousemodelsandpharmacologi- proliferative vasculardiseasesusingEPAC human diseases, suchchronicpainand (EPAC). exchange proteinsdirectlyactivatedbycAMP Research associate: Wei Lin Robichaux William Instructor: scientist: Wenli YangResearch FangMei Research assistantprofessor: LAB MEMBERS Science Advances. 6:eaay3566, 2020. of Notchandsuppression VEGF signaling. tive retinopathythroughcoordinatedactivation X. Epac1inhibitionamelioratesvasoprolifera- Toth, E.;Luo, P.; Li, Y. M.;Zhang, W.; andCheng, Liu, H.;Mei, F. C.; Yang, W.; Wang, H.; Wong, E.; 2019. of ClinicalInvestigation. 130:3732-3737, sulfonylurea-induced insulinsecretion. Journal β cell-intrinsic-arrestin1signalingenhances Cheng, X.;Chen, W.; Gurevich, V.; and Wess, J. Barella, L.;Rossi, M.;Zhu, L.;Cui, Y.; Mei, F.; FASEB J. 32:2212-2222, 2018. translocation andplasminogenactivation. regulates endothelial Annexin A2 cellsurface Yang, W.; Mei, F.C.; andCheng, X. EPAC1 KEY PUBLICATIONS IMMPACT REPORT • • • • 73 KEY PUBLICATIONS KEY PUBLICATIONS H.; Song, T.; Zhou, D.; Zheng, Y.; Zhang, L.; Z.; Shao, Wang, Y.; N.; Liu, M.; Su, Hulsurkar, Liao, F.; H.; Xu, M.; Han, M.; Gleave, Ittmann, W.; Wang, H.; W.* Androgen deprivation Li, and promotes neuroendocrine differentiation pathway angiogenesis through CREB-EZH2-TSP1 Nature Communications, in prostate cancers. author *corresponding 2018 Oct 4; 9(1):4080. X.; Li, Xiao, D.; X.; Feng, Zhou, Y.; S.; Liu, Chi, Knockdown of long H. Wang, Y.; W.; Zhao, enhances the sensitivity to non-coding HOTAIR progesterone in endometrial cancer by epigen- etic regulation of progesterone receptor isoform B.and Pharmacology. Cancer Chemotherapy 2019 Feb;83(2):277-287. D.; W.; Danielpour, L.; Li, Liao, Y.; Liu, D.K.; Lee, prostate carcinoma cells Neuroendocrine J. Xu, originate from the p63-expressing basal cells but not the pre-existing adenocarcinoma cells 2019 May;29(5):420- Cell Research. in mice. 422 LAB MEMBERS Lijuan Zhuo. Wang, Post-doctoral fellows: Zheng Yang Research assistant II: Han signaling in tumor progression and angio- genesis. cancer therapeutics. cancer therapeutics. mesenchymal transition. mesenchymal transition. cancer metastasis. cancer metastasis. •Epigenetic mechanisms of beta adrenergic •Lineage plasticity and acquired resistance to •New and mechanisms of epithelial- pathways Studying and targeting cancer metastasis and drug resistance metastasis and targeting cancer Studying as a critical pro- which is increasingly accepted drug resistance cess in cellular plasticity and Upon solid cancer types. of these two major, some ARPIs, to the acquisition of resistance cancers AR-positive prostate adenocarcinoma AR-low/negative aggressive neuroendo- become after becoming Similarly, crine prostate cancers. some NSCLC resistant to EGFR inhibitors, demonstrates phenotypes of small cell lung which is neuroendocrine in nature and cancer, NED is still poorly understood, very aggressive. and currently there are no effective treat- to prevent or overcome drug resistance ments, Li investigates the underlying Dr. related to NED. cellular plasticity and drug mechanisms of NED, mechanisms especially the roles and resistance, of action of several novel epigenetic regulators. RESEARCH PROJECTS •Mechanisms of action for novel regulators of Wenliang Li, PhD Li, Wenliang Associate Professor Targeting molecular links for angiogenesis and neuroendocrine differentiation, two prominent molecular links for angiogenesis and neuroendocrine differentiation, Targeting transcription of severalActivated CREB1 directly induces phenotypes in advanced prostate cancers. promotes GRK3 and HDAC2 genes involved in neuroendocrine differentiation (NED) or angiogenesis. CREB1 activa- an anti-angiogenesis factor. TSP1, at least in part through downregulating angiogenesis, which is critical for NED and angiogenesis induced by tion also enhances the PRC2 function of EZH2, Novel Several other players/pathways also contribute to both phenotypes. androgen derivation therapy. strategies targeting these pathways may be effective to treat neuroendocrine prostate cancers that are lethal with no effective treatment. Dr. Wenliang Li’s research programs are (1) Li’s Wenliang Dr. to the spread of tumor Cancer metastasis, is to lab Li’s Another research topic in Dr. to obtain critical new knowledge of cancer metastasis and drug resistance of human and (2) to identify new biomarkers cancer cells, and drug targets for the development of better therapeutics for human cancers. is responsible body, other parts of a patient’s cancer However, for over 90% of cancer death. the and metastasis is still poorly understood, current approaches to prevent or treat human metastatic cancers are mostly unsuccessful. medical there is a huge unmet Therefore, need to better understand cancer metastasis and to develop new therapies against cancer RNAi and cDNA genomics, Through metastasis. lab has identified Li’s Dr. functional screens, several but previously crucial unknown regula- novel Some of the tors for cancer metastasis. regulators control epithelial-mesenchymal tran- essential for while some others are sition (EMT), survival and proliferation of highly metastatic a devel- EMT, essential genes). cancer cells (i.e. is believed to play a key role opmental process, organ drug resistance, in cancer metastasis, Essential and stem cell phenotypes. fibrosis, genes for metastatic cancer cells may be the the rate-limiting key to understand colonization, Signaling pathways step of cancer metastasis. and molecular mechanisms of these novel regulators are under investigation with molecu- proteomic genomic, biochemical, cellular, lar, These studies and mouse models. approaches, are yielding critical new insights for cancer metastasis and facilitating the development of new therapeutics and biomarkers. investigate the mechanisms of cancer cell plas- Li Dr. In particular, ticity and drug resistance. studies how prostate cancers become resistant to new generations of androgen receptor path- and how non-small cell way inhibitors (ARPIs), lung cancers (NSCLC) become resistant to EGFR The common theme in this topic is inhibitors. to better understand and to target a process called neuroendocrine differentiation (NED), TEXAS THERAPEUTICS THERAPEUTICS TEXAS INSTITUTE 74 • IMMPACT REPORT TEXAS THERAPEUTICS INSTITUTE TEXAS THERAPEUTICS current efforts are focused on further optimizing arefocusedonfurther current efforts models ofcolorectal and ovariancancer. Our displayed robustanti-tumor activityinanimal their drugconjugates. The modifiedantibodies series ofanti-LGR4antibodiesandgenerated We havealsoidentifiedandcharacterizeda efficacy inpreclinicalmodelsofcoloncancer. LGR5 antibodiesshowedexcellentanti-tumor recently, weshowedthatdrugconjugatesofant- adenocarcinomas andcolorectalcancer. Most has amajorroleintheaggressivenessoflung In particular, weuncoveredthatRSPO3-LGR4 together toregulatecellgrowthandmigration. have nowuncoveredhowRSPOsandLGRswork for thesurvivalandgrowthofstemcells. We called R-spondins(RSPOs)thatareessential as receptorsofagroupstemcellfactors Previously, wediscoveredthatLGR4-6function survival ofnormalstemcellsandtumorcells. LGR6 (LGR4-6), thatplay critical rolesinthe surface receptorscalledLGR4, LGR5, and function andmechanismsofagroupcell cancer treatment. therapeutics forregenerativemedicineand ofnovel to thediscoveryanddevelopment cancer stemcellswillprovidecrucialknowledge anddifferentiationof normaland self-renewal the mechanismsthatgoverncontrolof profile andregulatorysystems. Understandingof similarity tonormalstemcellsinmolecular cells ortumor-initiatingcells, oftenbeargreat cancercells,renewing designatedcancerstem that makeupthebulkoftumor. These self- andprovidedaughter cells cells canself-renew heterogeneous inwhichonlyasubpopulationof indefinitely. Furthermore, tumortissuesarealso areprogrammedtodivide of cancerasthey tobethecells-of-origin for manytypes believed repair afterinjury. However, thesecellsarealso rate, suchasthegutandskin, andfortissue the maintenanceoftissueswithhighturnover the stemcellsreside. areessentialfor They types ofdifferentiatedcellsinthetissuewhere andgiverisetoalltheother can self-renew Our researchisfocusedondelineatingthe Adult stemcellsarespecializedthat CTL =controlexperiment(noFZD). –and+RSPO1=theabsence andpresenceofRSPO1, respectively. signal asaresultoftheligationLGR5withFZD. Bluerepresentsstainingofthenucleicells. arelocatednexttoeachother.signal onlyifthey Eachgreendotrepresentsanamplifiedfluorescence din1 (RSPO1)asshowntheproximityligationassay. Two moleculescanbelinked(ligated)togivea LGR5 directlyinteractswiththe Wnt receptorFrizzled(FZD)inthepresenceandabsenceofR-spon- Janice DavisGordonChairforBowelCancerResearch Professor (Jim)Liu,Qingyun PhD of cancertherapeutics Investigation ofnormalandcancerstemcellsforthediscovery Carmon, K.S.;Gong, X.;Lin, Q.; Thomas, A.; and KEY PUBLICATIONS •Optimization ofantibody-drugconjugates •Identification ofleadmoleculestargeting •Investigation oftherolesaberrantexpres- •Determination ofthefunctionandmechanism •Delineation ofsignalingmechanismsstem RESEARCH PROJECTS complex directly, asshowninthepicture. ered thatLGR5interactswiththe Wnt signaling cancers ofthedigestivesystem. We alsodiscov- all threeLGRreceptorsforthetreatmentof discovered anovelapproachthatcantarget other typesofmalignancies. Recently, wehave as potentialtreatmentforcolorectalcancerand these drugleadstargetingtheRSPO-LGRsystem types. treatment ofcolorectalandothercancer targeting theRSPO-LGRsystemfor therapeutics. the RSPO-LGRsystemasnovelanticancer metastasis oflungandcoloncancer sion oftheRSPOsincontroltumor cancer cellgrowth. of thereceptorsincontrolnormaland cell receptors. Ling Wu associates: WangshengSr. AliceYu,research Post-doctoral fellows:SoohyunPark, Jianghua Tu LAB MEMBERS 9769 (2018). catenin signaling. J. Biol. Chem. 293:9759- the fourR-spondinsinpotentiating Wnt/β- Q.J. Differentialactivitiesandmechanismsof Park, S.;Cui, J.; Yu, W.; Wu, L.;Carmon, K.S.;Liu, Biol Chem. 292:14989-15001(2017). cancer cellsviatheIQGAP1-Rac1pathway. J cell-cell adhesioninstemcellsandcolon myanov, K.A.;Liu, Q. J. LGR5receptorpromotes Moore, C.M.;Masuho, I.; Timson, D.J.;- Marte Carmon, K.S.;Gong, X.; Yi, J.; Wu, L.; Thomas, A.; Cancer Ther. recurrence.testinal tumorsandprevents Mol antibody-drug conjugateeradicatesgastroin- Z.; Liu, Q.;Carmon, K.S. (2016). LGR5-targeted Xiong, W.;An,X.; Azhdarinia,Ghosh,S.; Gong, A.; S A,U Wnt/beta-catenin signaling. ProcNatl Acad Sci orphan receptorsLGR4andLGR5toregulate Liu, Q. R-spondinsfunctionasligandsofthe 108:11452-11457 (2011). 15:1580-1590 (2016). IMMPACT REPORT • • • • 75 modification for organ-specific delivery modification for organ-specific Quorum sensing-guided drug delivery. •Quorum sensing-guided drug KEY PUBLICATIONS M.; Zhang, X.; Deng, W.; Gui, Xiong, Y.; Anami, K.* (2017) Tsuchikama, Z.; An, N.; Zhang, C.; C. Enzymatic Conjugation Using Branched Linkers Antibody–Drug for Constructing Homogeneous & Biomo - Organic Conjugates with High Potency. 5635–5642. 15, lecular Chemistry, X.; W.; Gui, M.; Xiong, C. Yamazaki, Y.; Anami, K.* (2018) Tsuchikama, Z.; An, N.; Zhang, Glutamic acid–valine–citrulline linkers ensure stability and efficacy of antibody–drug conju- 9:2512. Nature Communications, gates in mice, K.* Tsuchikama, - (2019) Transglu Y.; Anami, Methods in taminase-Mediated Conjugations, 2078:71–82. Molecular Biology, LAB MEMBERS Anami, PhD, Post-doctoral fellows: Yasuaki PhD Aiko Yamaguchi, PhD, Chisato Tsuchikama, Roeder Travis Research assistants: high plasma stability, rapid drug release, and rapid drug release, high plasma stability, enhanced permeability to the brain. branched chemical linkers for constructing multi-loading ADCs. With our technology platform in hand, we With our technology hand, platform in Modulation of the ADC function by chemical •Modulation of the Structural optimization of ADC linkers for •Structural optimization of are currently pursuing next-generation ADCs are currently pursuing next-generation for combating the cancer drug resistance These are unsolved and heterogeneity issues. issues in cancer chemotherapy leading to discontinuation of medication and recurrence Another research direction in of malignancy. delivery ADC my lab is to improve antibody and We efficiency to the brain and brain tumors. help ADC linkers will envision that our novel not only ourselves but also other researchers establish various approaches for overcoming such unsolved issues in cancer management. RESEARCH PROJECTS and evaluation of novel synthesis, •Design, of two distinct drug molecules onto a single of two distinct drug molecules This dual-loading linker antibody (Figure 1). ADCs with of enables construction of a variety drug-to-antibody high homogeneity and defined have demonstrated that our dual- We ratios. exertADCs greater therapeutic effect in drug mouse models of human breast cancer than can be achieved by conventional single-drug ADCs one of the dual-drug Notably, variants. was more efficacious in a clinically relevant, heterogeneous breast tumor model than a com- in ADCs (manuscript bination of two single-drug these technologies together, Taken preparation). design ADC molecular could add flexibility to which ADC therapeutic efficacy, and maximize may help increase success rates in preclinical studies. Linker and conjugation technologies for generating novel for generating novel technologies and conjugation Linker cancer (ADCs) toward innovative antibody-drug conjugates therapeutics Kyoji Tsuchikama, PhD Kyoji Tsuchikama, Assistant Professor Antibody-Drug Conjugates (ADCs) represent a My research group is focused on the develop- Novel ADC linker technologies developed by our lab. (a) Construction of dual-drug ADCs with high homogeneity using branched linkers. (b) In vivo comparison linkers. ADCs with high homogeneity using branched (a) Construction of dual-drug ADC linker technologies developed by our lab. Novel All tumor-bearing mice were treated with a admixed xenograft mouse model (n = 5). ADCs equipped with single or dual drugs in the JIMT-1/MDA-MB-231 of ADC (3 mg/kg) at Day 0 (indicated with a black arrow). single dose of each rapidly growing class of anticancer therapeutics. ADCs As demonstrated with 5 FDA-approved Mylotarg®, Besponsa®, Kadcyla®, (Adcetris®, ADCs and Polivy®) and more than 80 promising successful clinical outcomes in clinical trials, and clini- ADCs have inspired scientists using cians to further advance this new molecular ADCs format for effective treatment of cancers. deliver anticancer drugs (payloads) selectively to blood cancer cells and solid tumors while use of enabling the avoiding healthy tissues, highly active payloads that are too toxic to be ADC chemical linker connecting The used alone. the antibody and the payload molecule needs to selectively deliver and release payloads only the use of properly Thus, at the tumor sites. ADC linkers is a key for successful designed ADC-based chemotherapy. implementation of by taking ADC linkers ment of novel chemical advantage of the power of organic chemistry, We and chemical biology. medicinal chemistry, have developed a glutamic acid-valine-citrulline ADC linker. tripeptide linker as a new-generation Unlike the conventional valine-citrulline linker that is known to undergo degradation in mouse our tripeptide linker is stable in circulation, maximizing both human and mouse plasma, ADC circulation stability and therapeutic ef- ADC we developed dual-loading Recently, ficacy. enabling simple and easy installation linkers, TEXAS THERAPEUTICS THERAPEUTICS TEXAS INSTITUTE 76 • IMMPACT REPORT TEXAS THERAPEUTICS INSTITUTE TEXAS THERAPEUTICS of the art technologies areusedinourstudies of theart proteolytic impairment ofantibodyhinge. State triggeredby nisms ofcancerimmune evasion proteolytic impairmentandtoidentifymecha - cancer patientstodeterminefactorsinfluencing models, andstudieswithclinicalsamplesfrom vitro 2Dand3Dcellco-cultures, mousetumor array ofexperimentalapproachesincluding in ment. To testourhypothesis, weemployawide to animmunesuppressivetumormicroenviron- antibody anticancerimmunitybutalsoleads hinge cleavageofantibodiesnotonlyweakens metalloproteinases (MMPs). Suchproteolytic impairment throughahingecleavagebymatrix microenvironment aresusceptibletoproteolytic tumor associatedantigens(TAA) inthetumor we hypothesizethatantibodiesrecognizing byothers,on ourrecentfindingsandreports and reducedantitumorefficacyinvivo. Based effector functionagainstcancercellsinvitro hinge cleavageshowedalossofimmune (anti-HER2antibody)withasingle pertuzumab tumor microenvironment. Trastuzumab and lytic impairmentofantibodyIgGinthe ofproteo- demonstrated theprevalence as ahallmarkofcancer. Ourresearchhas immunity forimprovementofcancertreatment. therapeutic strategiestomodulateanticancer ofantibodyimmunityand develop evasion are centeredonbetterunderstandingoftumor cancer patients. Ourcurrentresearchprograms these cancertargetedtherapiestobenefitmore forimprovementof paramount importance resistance totherapeuticantibodiesisof Understanding themechanismofcancer therapeutic antibodiesarewidelyreported. both innateandacquiredresistancetothese treatment ofmanytypescancer. However, factor VEGF, havebeensuccessfullyusedfor targetingtumor angiogenesis and bevacizumab antibodies, suchastrastuzumabagainstHER2 types ofcancer. Tumor targetingmonoclonal shown clinicalsuccessfortreatmentofvarious drug modalityforcancertreatmentandhave Cancer immune evasion isrecognized Cancer immuneevasion Monoclonal antibodiesarebecomingamajor Zhang.* (2019)Potentneutralizingantibodies Zhang.* Casimiro; Kalpit Vora; Zhiqiang An; Ningyan Benjamin J. Doranz; J.Andrew Bett;DaniloR. gina T. JenniferM. Salazar; Pfaff; Trevor Barnes; Geor- Elizabeth A.QihuiWang; Thoryk; DiStefano; Leike Li; Weixu DanielR. Meng;MelanieHorton; KEY PUBLICATIONS platformtechnologiesfor discoveryof •Develop •Understand mechanismsofcancerimmune RESEARCH PROJECTS immunotherapies. ofeffectiveanticancer targets fordevelopment molecular cellular immunityandtoidentifykey ofantibodyand mechanisms ofcancerevasion long-term goalofmyresearchistounderstand andpreclinicaldevelopment.evaluation The select novelanticancerantibodiesforfunctional todiscoverand antibody platformtechnology antibodies. We haveestablishedamonoclonal (FACS),cell sorting andsinglecellcloningof mass spectrometry, fluorescenceactivated such ashighcontentfluorescenceimaging, Associate Professor Zhang,Ningyan PhD blue forN. FromL. Liet. al. (2019) PloSPathogens. V173, D177)onF0, G0β-strands, andtheG0H0looponEproteindomainI. Atoms coloredredforO, with d462areshownasgreenspheres. (B, Enlargedview ontheright)showsepitoperegion(V160, black line(A, ontheleft)showsboundaryofasingleasymmetric unit. The residuesthatinteract Antibody d462epitopemappedonenvelope (80E)proteinstructureofdenguevirus(PDB, 4CBF). The modulation ofanticancerimmunity Cancer resistancemechanismstotherapeuticantibodiesand therapeutic antibodies. suppression. Zhiqiang An’s group Zhiqiang An’s Post-doctoral fellows:SeethelistunderDr. Xuejun Fan, MD, PhD; Wei Xiong, PhD Research associate/scientists:HuiDeng, MS; LAB MEMBERS insight.125094. Clinical Investigation Insight, doi/10.1172/jci. Driver ofMalignant Tumor Growth. Journal of Scherer. (2019)HumanEndotrophinasa Zhang;Zhiqiang Ningyan An; andPhilippE. Adan Rios; Yujun Chang; Anneliese Gonzalez; Zheng Liu;PerEysteinLønning;NilsHalberg; Ruth Gordillo; Wei Xiong;HuiDeng;Xiao- ChristineM.Dawei Bu;ClairCrewe; Kusminski; Oncogene, doi:10.1038/s41388-018-0565-9. Stimulating Tumor Angiogenesis.and Metastasis by SimultaneouslyEnhancingCancerCell (2019)EGFL6PromotesBreastCancer Zhang.* X. Zhang; Anil K. Sood;Zhiqiang An; Ningyan Jingnan An; Du;XuejunFan; Yi Y. Wang; C. Ivan; e1007716, doi:10.1371/ppat.1007716. target diverseepitopes. PloSPathogens, elicited bydenguevaccineinrhesusmacaque IMMPACT REPORT • • • • 77 enter tional a C ransl e ervic T

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Proteins are the essential functional the essential functional are Proteins linical eomics rot C P participatebiomolecules that array of in a vast implicated activities and are physiological cellular Disease in all aspects of disease mechanisms. alterations may reflect associated proteome structure, expression, on changes in protein as localization, and polymorphism, as well status. post-translational modifications (PTMs) of a dynamic information can deliver Proteomics in a complex system and thereby profile protein cellular function of a vibrant picture provide under biological conditions. Furthermore, can identify steady proteomics quantitative or perturbation-induced alterations proteome associated with a disease status or biological and to translational state, and is highly relevant state center provides clinical applications. Our of the art services proteomics to support basic, main The translational, and clinical research. or services label-free profiling, include protein analysis, therapeutic label-based quantitative characterization, and essential PTM protein a broad the capability to analyze have We analysis. or clinical specimens, from range of research including to complex mixtures, purified proteins cell and tissue extracts, plasma/serum, and other We also provide biofluids or biological samples. support collaborative advanced through more and efforts, discovery such as biomarker analysis, glycoproteomics/glycomics verification, The center contains profiling. and microbiome instrumentation and well-trained the innovative an integrated proteomics personnel to provide service, mass including sample preparation, analysis, and bioinformatics data spectrometric processing. the optimized therapeutic antibodies with the therapeutic antibodies the optimized to novel basic research ultimate goal of translating therapies. and

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Antibody therapeutics represents a major Antibody therapeutics represents To accomplish IMM’s strategic goal of strategic goal accomplish IMM’s To ntibody xpression A E diseases in combating human breakthrough the pharmaceutical though Even including cancer. in the center and biotechnology industries are stage of drug and development, discovery engaged increasingly are academic researchers new antibody drug candidates. in discovering of some of the promising advancement However, from antibodies in the early stage of discovery laboratories is often hindered academic research the lack of access to the expertiseby and for antibody engineering required infrastructure antibody Our key technologies. and other related serviceengineering and expression center offers the services to fill the gap of the much needed expertise of monoclonal in early discovery antibodies and lead optimization for the research of and drug The objective communities. discovery technical supportthe service center is to provide and services molecular to antibody identification, and purification. cloning, antibody expression, the service generated from center will Results to attract ability the collaborators’ strengthen of external funding to continue development IMM Service Centers Service IMM

protein technologies and animal models. Our animal models. Our technologies and protein the latest service goal is to provide center highest quality servicestechnology and the to our while operating in a colleagues and customers Service Centers are IMM’s manner. cost-effective expertsresearch technologies in the by top staffed offered. support high quality and effective providing initiated have we services capacity, for our research our to furthera systematic process improve to our faculty and and to provide infrastructure The customers access to cutting–edge technology. establishment of key service centers at UTHealth- commitment. IMM is a critical component of this T 78 • IMMPACT REPORT UTHealth andexternalorganizations. chargetoallresearch investigatorsservice from areOur instruments available onafee-for- design, interpretation, andtroubleshooting. andconsultation forexperimental cell sorting, Center offers FACS acquisitionandanalysis, cells persecond.The Flow Service Cytometry fluorescent signalsfrom thousandsofindividual allows simultaneousacquisitionofupto19 Thecurrent to besorted. instrumentation cells andadditionallyisolatecellpopulations rare populationsof gather informationonvery timeframeand number ofsamplesinashort allowinstruments researchers toevaluate alarge genetic manipulations. response and tospecificstimulisuchasdrugs like relative size, complexity, celltype,and can bemeasured todeterminecellularproperties wavelengths. Thefluorescenceof lasersvarying are fluorescently labelledandthenpassedinfront fluid. Typically, a variety ofcellularcomponents the characteristicsofindividualcellssuspendedin F low These specialized multicolorcellanalysis Flow isatechniqueusedtoanalyze cytometry C ytometry S ervice C entr stem cellsresearch. different aspectsofmicrosurgery, cellculture, and in cell linesandintellectual/technicalsupport CRISPR/Cas9 genomeediting,derivation ofnew ofthefacilityalsoincludegenetargeting, services of genetically-engineered miceandrats,the andre-derivationproduction, cryopreservation, cell differentiation studies. In additiontothe generation ofknock-out/knock-inmiceandfor are highlyeffective forthe in thelaboratory basis. organizations onafee-for-service investigators from UTHealth andexternal knock-out mouseanimalmodelsforallresearch It hasgeneratedover transgenicand 800new centerwhichwasestablishedin1998. service Center operatesa Transgenic andStem Cells S T Research Building. located onthethird floorofthe Fayez S. Sarofim imaging filescanproduce 3D Models. We are are available. STLfiles, SolidWorks, ormedical Shorematerials withvarying Avalues (hardness) 3D printerswithlargeprintbeds.Awiderangeof based high-resolution Stratasys J750(14micron) 450mc) thermoplasticandmulti-color, resin- models. We have bothtraditionalFDM(Fortus surgical tools,inprototype orfinalproduction 3D printedmodelsofhumanorgansandnovel We 3Dprintingservices. state-of-the-art provide N ervice ransgenic ano The stemcelllinesthathave beenderived Our Immunology andAutoimmune Diseases Nano 3DPrinting Centerprovides Service 3DP C entr

rinting and S tem S ervice C ell C entr IMMPACT REPORT • • • • 79 $22,713,220 $25,000,00 $22,330,042 $21,662,579 62 59 57 56 $18,551,132 $18,212,270 53 IMM By the Numbers By IMM Excludes all ARRA funds Excludes all Sponsored Projects based on award received Service Centers and Endowments/Gifts based on expenses $15,000,000 $20,000,000 Note - 60 30 40 50 $10,00,000 Number of Faculty Number 20 Total Funds Supporting Research Funds Supporting Total $5,000,000 10 Endowment/Gifts Service Center Sponsored Projects 0 0 2018 2019 2017 2016 2015 FY 17 FY 18 FY 19 FY 16 FY 15 80 • IMMPACT REPORT IMM By theNumbers 3% Total Expenses Supporting Research 11% 5% 66% 15% Service Centers Industry Foundations State Government Federal Government IMMPACT REPORT • • • • 81 Gift Report Gift Thank you to all of our supporters! Elizabeth Eikenburg Elizabeth Inc. Keller, A. P. Anne Pullen MD Jr., and Carlos Hamilton, Carolyn Collie, Jr. and Robert Barbara Foundation Family Brazelton McLean Mary Hale Robinson Marian McDonald Marilyn Simon Debra Harris Lucile and Louana Frois Ted Fund Barry Barbara and Philanthropic Lewis The Allen Joe and Helen Mary Errera and Robert Holmes Kay and Ned MA PhD, Gorenstein, and David Deborah Foundation Adler Ltd Growers BU Horne Mrs. Howard Alan Dale Rowan Eloise Allen Nancy White Sara Ann Trammell Jr. Seale, Robert and Chalon Fontaine Jurek Roberta III Baker and James Susan Glassell Clare Zhiqiang An, PhD and Alan Baden Betty Oldham and Dudley Judy Perkins and Richard Judith McDonald and John Patricia Foundation Hamman and Mary Josephine George New Gifts and Bequests Fiscal Year 2019 Fiscal and Bequests New Gifts 82 • IMMPACT REPORT Dr. Edward Randall,Jr. Memorial Fund Marjorie B.Poyner andHerbert F. Poyner, Jr. Endowment for Medical Research D. Dudley andJudy White Oldham Research Fund Hans J.Muller-Eberhard, MD,PhD andIrma Gigli, MDDistinguished Muller-Eberhard Memorial Lecture Series George andCynthia Mitchell Distinguished ChairinNeurosciences Rochelle andMax LevitChairintheNeurosciences Kozmetsky Family ChairinHuman Genetics Nancy andRichKinderDistinguished Chairin Cardiovascular Disease Research William S.Kilroy, Sr. Distinguished University ChairinPulmonary Disease The Carolyn Frost Keenan Professorship inCardiovascular Disease Research Jerold B.KatzDistinguished Professorship inStem CellResearch IMM General Endowment ElizabethMary Holdsworth Distinguished University ChairinMetabolic and George Josephine andMary Hamman Foundation Distinguished Professorship in Annie andBobGraham Distinguished ChairinStem CellBiology Janice Davis Gordon Chairfor Bowel CancerResearch Kay andBen Fortson Distinguished ChairinNeurodegenerative Disease Research Linda andRonny Finger Foundation Distinguished Chairin The Laurence and Johanna Favrot Distinguished Professorship inCardiology John S.Dunn Research Scholars Cullen ChairinMolecular Medicine E.Bovay,The Harry Jr. Distinguished University Chairin Metabolic E.Bovay,Harry Jr. Lecture Series inMolecular Medicine Becker Family Foundation Professorship inDiabetes Research Medicine EndowmentsInstitute of Molecular in theInstitute ofMolecular Medicine forPrevention ofHuman Diseases Chair inImmunology Inflammatory Disease Research Cardiovascular Research Neuroimmunologic Disorders Disease Research IMMPACT REPORT • • • • 83

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who Heart Disease Research Disease Heart Foundation Halsell the Ewing from Research Disease Shavonnah Roberts Schreiber Women’s Health Endowment Health Women’s Schreiber Roberts Shavonnah in Professorship Distinguished Foundation JerryMaury Rubenstein and The Fund Research Memorial Runnells Pierce Fund Endowment Research Cell Stem Initiatives New J. Sands Rodney Chair University Distinguished Wallace G. and Lorine C. Harold Medicine in Molecular Professorship Distinguished and Mary Mischer Walter Chair in Chemistry University Distinguished Welch A. Robert in Chemistry Sciences Related Endowment and Foundation Welch The Tribute in Research Chair in Cardiovascular Distinguished Willerson T. James Chair in Neurodegenerative Distinguished Zilkha and Michael Nina 84 • IMMPACT REPORT