DOCSLIB.ORG

Characterization of the DJ-1 Knockout Rat Model of Parkinson's Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Characterization of the DJ-1 Knockout Rat Model of Parkinson's Disease Characterization of the DJ-1 Knockout Rat Model of Parkinson’s Disease A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Ph.D.) in the Neuroscience Graduate Program of the College of Medicine 2019 By Tara Leigh Kyser B.S., Ursinus College Advisor: Kim B. Seroogy, Ph.D. Committee Chair: Mark Baccei, Ph.D. Christina Gross, Ph.D. Michael Williams, Ph.D. David Yurek, Ph.D. Abstract Parkinson’s disease (PD) is a complex neurodegenerative disorder with a plethora of symptoms categorized as motor and non-motor. Historically, research on PD has focused mainly on degradation of the nigrostriatal pathway. However, degeneration of additional brainstem regions, including the locus coeruleus (LC) and dorsal raphe nucleus (DRN), and dysfunction of their associated noradrenergic and serotonergic neurotransmitter systems, respectively, also contribute to disease pathology. Nevertheless, the etiology of the vast majority of PD cases remains unknown. The overall goal of our work was to examine the relatively novel DJ-1 knockout (KO) rat model of PD in an effort to expand our knowledge of the manifestation and progression of PD. Complete loss of the protein DJ-1 leads to an autosomal recessive form of PD. The DJ-1 KO rat was created with the objective of generating an animal model with a more robust PD phenotype than seen previously in DJ-1 KO mice. Although a few studies on these mutant rats have noted some promising PD-like features, they have not always been in agreement. Here, we conducted a more thorough analysis of the DJ-1-deficient rat model, hypothesizing that we would uncover aberrant motor and non-motor behaviors, altered neurotransmitter levels and reduced neuronal survival in PD-relevant brain regions. In Aim 1, we performed a battery of motor and non-motor tasks at various ages to expand the behavioral characterization of the DJ-1 KO rat. Consistent with a PD phenotype, the DJ-1 KO rats demonstrated a reduction in rears, stride length, and grooming time, compared to wild-type (WT) control rats. However, the DJ-1-deficient rats took more steps than WT controls in several motor tasks, inconsistent with PD-like behavior. The non-motor findings were also mixed, in that DJ-1 KO rats exhibited deficits in short-term memory, but also better olfactory detection and increased sucrose intake during the sucrose preference task. In Aim 2, we examined monoamine levels using neurochemistry to determine if DJ-1 KO rats showed altered i levels of monoamines in brain regions associated with PD. We used immunohistochemistry and unbiased stereology to examine the substantia nigra pars compacta, LC, and DRN for monoaminergic neuronal degeneration. Depending on age, we detected increases in the dopamine metabolite 3,4 dihydroxyphenylacetic acid in the striatum and of the serotonin metabolite 5-hydroxyindoleucetic acid in the ventral midbrain and hippocampus of DJ-1-deficient rats. Norepinephrine (NE) levels in the hippocampus of DJ-1 KO rats were lower than controls. DJ-1 KO rats demonstrated reduced numbers of noradrenergic LC neurons than WT rats and a loss of serotonergic neurons in the DRN, regardless of age. In Aim 3, because of the association of neuroinflammation with PD, we evaluated activated microglia in several PD- related brain regions in DJ-1 KO rats. Only the LC displayed activated microglia when compared to WT rats, suggesting limited involvement of detrimental microglial mechanisms in the DJ-1- deficient brain. Overall, DJ-1-deficient rats demonstrate a PD-like phenotype in several behavioral, neurochemical and morphological aspects of the disease. Moreover, the data suggest that DJ-1 KO rats will be particularly useful in investigating prodromal stages of PD. ii iii Acknowledgements Over the course of my dissertation I have had people who have given me guidance and support, and I would like to thank these individuals. First, I would like to thank my advisor Dr. Kim Seroogy. Thank you for allowing me to join the lab. I appreciate all the guidance you have given me and for allowing me to follow my interests in the lab. Thank you for all the advice you have given me and for making me a better scientist. I wish to thank my committee members Mark Baccei, Michael Williams, Nina Gross, and David Yurek for all of their helpful suggestions and individual guidance. I want to thank Mark Baccei for being the head of my committee and helping me through the graduation process. I appreciate at his advice and support as both a committee member and director of the Neuroscience Graduate Program. I would like to thank Michael Williams for his help with the behavioral testing as well as statistical analysis. Thanks to Nina Gross for being on my committee and all her thoughtful questions that made my dissertation better. Lastly, I would like thank David Yurek for traveling the long distance to the University of Cincinnati for the committee meetings and for sharing your vast knowledge of Parkinson’s disease I would like to thank the Neuroscience Graduate Program for accepting me into the program. I want to thank the past (Deb Cummins and Sharon Weber) and present (Ana Madani) program coordinators and manager for their help with a lot of the paperwork and for making sure I turned everything in on time. Thank you to the past (Jim Herman and Kim Seroogy) and present (Mark Baccei) program directors for allowing me the opportunity to conduct research at UC. Also, thanks to my fellow students for shared knowledge, encouragement, and the good times we shared. iv To members of the Seroogy Lab, past and present, thank you for all of your help in lab and without you I would not have gotten this far. Kerstin Lundgren, thank you for being the anchor in lab and teaching me a lot of valuable laboratory techniques such as in situ hybridization. To Ann and Sarah, thank you for all the laughs and being very supportive lab mates. I would like to thank all of the undergraduates who helped me over the years, and most especially Adam Dourson for helping me greatly in the last couple years of my dissertation work. Importantly, I wish to acknowledge the financial support of NIH and the James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders. Last, but not least, I would like to thank my family, friends, and dog Ollie. Thanks to my mom and dad for having faith in me and being supportive of my pursuits. To my Aunt Colleen and Grandmom, thank you for driving all the way out to Cincinnati to support me during my defense. And to the rest of my family who could not make it out, thank you for your love and encouragement. To my dog, Ollie, thank you for all the cuddles and being the best dog a person could ask for. Thanks to Becky Bailey, for going through this graduate student process with me and listening to me when I needed it the most. To Kenton Woodard, thank you for picking me up when I was down and for always being there for me no matter how far we are from each other. Last, but definitely not least, thanks to Amanda Stover. I really could not have gotten through this whole process without you. You are there for me through thick and thin, making me laugh and letting me know that you have faith in me when I had lost faith in myself. I look forward to being there for you while you go through your own dissertation process. v Table of Contents Abstract i Acknowledgements iv List of Tables and Figures 3 Abbreviations 5 Chapter 1: Introduction Parkinson’s disease 10 Risk factors for Parkinson’s disease 16 Animal models 22 The substantia nigra pars compacta and Parkinson’s disease 35 The dorsal raphe nucleus and Parkinson’s disease 38 The locus coeruleus and Parkinson’s disease 41 Olfaction and Parkinson’s disease 43 Depression and Parkinson’s disease 44 Anxiety and Parkinson’s disease 45 Cognitive Impairment and Parkinson’s disease 46 DJ-1 and Parkinson’s disease 47 Objectives 50 Specific Aims 50 References 51 Chapter 2: Characterization of Motor and Non-Motor Behavioral Alterations in the Dj-1 (PARK7) Knockout Rat Abstract 132 Introduction 133 Methods 136 Results 143 Discussion 156 References 164 1 Chapter 3: Altered Monoamine Levels and Cell Degeneration of Monoaminergic Nuclei Abstract 178 Introduction 179 Methods 182 Results 186 Discussion 193 References 201 Chapter 4: Evaluation of Activated Microglia in Aged DJ-1 Knockout Rats Abstract 211 Introduction 212 Methods 216 Results 219 Discussion 224 References 227 Chapter 5: General Discussion Discussion 239 Limitations and Caveats 244 Future Studies/Conclusions 246 References 247 2 List of Tables and Figures Chapter 1 Table 1. List of known non-motor symptoms in Parkinson’s disease 13 Table 2. Braak staging of Lewy body pathology 14 Table 3. Environmental risk factors associated with Parkinson’s disease 20 Table 4. Genetic risk factors of Parkinson’s disease 21 Chapter 2 Figure 1. Evaluation of spontaneous activity in DJ-1 KO and WT rats 145 at 4, 7, and 13 months of age. Figure 2. Assessment of sensorimotor changes during the adhesive 146 removal task at 4,7, and 13 months of age for WT and DJ-1 KO rats Figure 3. Evaluation of postural instability in the adjusting step task at 4, 147 7, and 13 months of age for WT and DJ-1 KO rats Figure 4. Analysis of gait changes in WT and DJ-1 KO rats at 2 and 13 148 months of age Figure 5.
Load more

Recommended publications
  • Knockout Rat Models Mimicking Human Atherosclerosis Created By
    www.nature.com/scientificreports OPEN Knockout rat models mimicking human atherosclerosis created by Cpf1-mediated gene targeting Received: 23 September 2018 Jong Geol Lee1,2,3, Chang Hoon Ha2,4, Bohyun Yoon2, Seung-A. Cheong1, Globinna Kim1,2,4, Accepted: 8 January 2019 Doo Jae Lee2, Dong-Cheol Woo1,2,4, Young-Hak Kim5, Sang-Yoon Nam3, Sang-wook Lee1,6, Published: xx xx xxxx Young Hoon Sung1,2,4 & In-Jeoung Baek1,2,4 The rat is a time-honored traditional experimental model animal, but its use is limited due to the difculty of genetic modifcation. Although engineered endonucleases enable us to manipulate the rat genome, it is not known whether the newly identifed endonuclease Cpf1 system is applicable to rats. Here we report the frst application of CRISPR-Cpf1 in rats and investigate whether Apoe knockout rat can be used as an atherosclerosis model. We generated Apoe- and/or Ldlr-defcient rats via CRISPR-Cpf1 system, characterized by high efciency, successful germline transmission, multiple gene targeting capacity, and minimal of-target efect. The resulting Apoe knockout rats displayed hyperlipidemia and aortic lesions. In partially ligated carotid arteries of rats and mice fed with high-fat diet, in contrast to Apoe knockout mice showing atherosclerotic lesions, Apoe knockout rats showed only adventitial immune infltrates comprising T lymphocytes and mainly macrophages with no plaque. In addition, adventitial macrophage progenitor cells (AMPCs) were more abundant in Apoe knockout rats than in mice. Our data suggest that the Cpf1 system can target single or multiple genes efciently and specifcally in rats with genetic heritability and that Apoe knockout rats may help understand initial- stage atherosclerosis.
    [Show full text]
  • UW-Madison Undergraduate Symposium || Abstracts 2014
    ABSTRACTS 2014 Undergraduate Symposium Celebrating research, creative endeavor and service-learning We would like to thank our major sponsors and partners: Brittingham Trust General Library System Institute for Biology Education McNair Scholars Program Morgridge Center for Public Service Office of the Provost Undergraduate Academic Awards Office Undergraduate Research Scholars Program University Marketing Wisconsin Union The Writing Center 2014 Undergraduate Symposium Organizing Committee: Jane Harris Cramer, Maya Holtzman, Svetlana Karpe, Kelli Hughes, Linda Kietzer, Laurie Mayberry, Aaron Miller, Christopher Olsen, Janice Rice, Amy Sloane, Julie Stubbs, Malika Taalbi, Beth Tryon, and Berit Ness (coordinator). A special thanks is also extended to Stephanie Diaz de Leon of The Wisconsin Union; Rosemary Bodolay, Patricia Iaccarino, Carrie (Carolyn) Kruse, and Pamela O’Donnell at College Library; and Jeff Crucius of the Division of Information Technology. Cover photos courtesy Office of University Communications and the Undergraduate Symposium Committee ii Abstracts and Art Statements University of Wisconsin–Madison April 10, 2014 • Union South THE SHORT AND DIFFICULT LIFE OF WALES’ DEVOLVED GOVERNMENT: WAS IT ALWAYS A LEGITIMATE INSTITUTION? Lucille Abrams, Yoshiko Herrera (Mentor), Political Science The construction of the regional, or devolved, government of Wales, as well as its corresponding governing body, the National Assembly for Wales, was a protracted process. Through library research, I sought to find the reasons for this dif- ficulty and ask if Welsh citizens believed the Assembly to be a valid, or legitimate, political institution. The political history of the United Kingdom, Wales’ individual history, and analysis of voter turnout at the first Assembly election, contribute to answering this question. The Assembly did not suffer from a lack of legitimacy but from an apathetic and alienated constitu- ency.
    [Show full text]
  • Introducing Gene Deletions by Mouse Zygote Electroporation of Cas12a/Cpf1
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2019 Introducing gene deletions by mouse zygote electroporation of Cas12a/Cpf1 Dumeau, Charles-Etienne ; Monfort, Asun ; Kissling, Lucas ; Swarts, Daan C ; Jinek, Martin ; Wutz, Anton Abstract: CRISPR-associated (Cas) nucleases are established tools for engineering of animal genomes. These programmable RNA-guided nucleases have been introduced into zygotes using expression vectors, mRNA, or directly as ribonucleoprotein (RNP) complexes by different delivery methods. Whereas mi- croinjection techniques are well established, more recently developed electroporation methods simplify RNP delivery but can provide less consistent efficiency. Previously, we have designed Cas12a-crRNA pairs to introduce large genomic deletions in the Ubn1, Ubn2, and Rbm12 genes in mouse embryonic stem cells (ESC). Here, we have optimized the conditions for electroporation of the same Cas12a RNP pairs into mouse zygotes. Using our protocol, large genomic deletions can be generated efficiently by electroporation of zygotes with or without an intact zona pellucida. Electroporation of as few as ten zygotes is sufficient to obtain a gene deletion in mice suggesting potential applicability of thismethod for species with limited availability of zygotes. DOI: https://doi.org/10.1007/s11248-019-00168-9 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-181145 Journal Article Published Version The following work is licensed under a Creative Commons: Attribution 4.0 International (CC BY 4.0) License. Originally published at: Dumeau, Charles-Etienne; Monfort, Asun; Kissling, Lucas; Swarts, Daan C; Jinek, Martin; Wutz, Anton (2019).
    [Show full text]
  • Athe Characteristics of Glucose Metabolism in the Sulfonylurea
    Zhou et al. Molecular Medicine (2019) 25:2 Molecular Medicine https://doi.org/10.1186/s10020-018-0067-9 RESEARCHARTICLE Open Access aThe characteristics of glucose metabolism in the sulfonylurea receptor 1 knockout rat model Xiaojun Zhou1†, Chunmei Xu1†, Zhiwei Zou2, Xue Shen3, Tianyue Xie3, Rui Zhang1, Lin Liao1* and Jianjun Dong2* Abstract Background: Sulfonylurea receptor 1 (SUR1) is primarily responsible for glucose regulation in normal conditions. Here, we sought to investigate the glucose metabolism characteristics of SUR1−/− rats. Methods: The TALEN technique was used to construct a SUR1 gene deficiency rat model. Rats were grouped by SUR1 gene knockout or not and sex difference. Body weight; glucose metabolism indicators, including IPGTT, IPITT, glycogen contents and so on; and other molecule changes were examined. Results: Insulin secretion was significantly inhibited by knocking out the SUR1 gene. SUR1−/− rats showed lower body weights compared to wild-type rats, and even SUR1−/− males weighed less than wild-type females. Upon SUR1 gene knockout, the rats showed a peculiar plasma glucose profile. During IPGTT, plasma glucose levels were significantly elevated in SUR1−/− rats at 15 min, which could be explained by SUR1 mainly working in the first phase of insulin secretion. Moreover, SUR1−/− male rats showed obviously impaired glucose tolerance than before and a better insulin sensitivity in the 12th week compared with females, which might be related with excess androgen secretion in adulthood. Increased glycogen content and GLUT4 expression and the inactivation of GSK3 were also observed in SUR1−/− rats, which suggested an enhancement of insulin sensitivity. Conclusions: These results reconfirm the role of SUR1 in systemic glucose metabolism.
    [Show full text]
  • Reproductive Technologies for the Generation and Maintenance Of
    Journal of Reproduction and Development, Vol. 64, No 3, 2018 —SRD Innovative Technology Award 2017— Reproductive technologies for the generation and maintenance of valuable animal strains Takehito KANEKO1–3) 1)Division of Science and Engineering, Graduate School of Arts and Science, Iwate University, Iwate 020-8551, Japan 2)Department of Chemistry and Biological Sciences, Faculty of Science and Engineering, Iwate University, Iwate 020-8551, Japan 3)Soft-Path Science and Engineering Research Center (SPERC), Iwate University, Iwate 020-8551, Japan Abstract. Many types of mutant and genetically engineered strains have been produced in various animal species. Their numbers have dramatically increased in recent years, with new strains being rapidly produced using genome editing techniques. In the rat, it has been difficult to produce knockout and knock-in strains because the establishment of stem cells has been insufficient. However, a large number of knockout and knock-in strains can currently be produced using genome editing techniques, including zinc-finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) system. Microinjection technique has also contributed widely to the production of various kinds of genome edited animal strains. A novel electroporation method, the “Technique for Animal Knockout system by Electroporation (TAKE)” method, is a simple and highly efficient tool that has accelerated the production of new strains. Gamete preservation is extremely useful for maintaining large numbers of these valuable strains as genetic resources in the long term. These reproductive technologies, including microinjection, TAKE method, and gamete preservation, strongly support biomedical research and the bio-resource banking of animal models.
    [Show full text]
  • Generation of Hprt-Disrupted Rat Through Mouse←Rat ES Chimeras Ayako Isotani1,2, Kazuo Yamagata2,†, Masaru Okabe2 & Masahito Ikawa1,2
    www.nature.com/scientificreports OPEN Generation of Hprt-disrupted rat through mouse←rat ES chimeras Ayako Isotani1,2, Kazuo Yamagata2,†, Masaru Okabe2 & Masahito Ikawa1,2 We established rat embryonic stem (ES) cell lines from a double transgenic rat line which harbours Received: 03 February 2016 CAG-GFP for ubiquitous expression of GFP in somatic cells and Acr3-EGFP for expression in sperm Accepted: 22 March 2016 (green body and green sperm: GBGS rat). By injecting the GBGS rat ES cells into mouse blastocysts Published: 11 April 2016 and transplanting them into pseudopregnant mice, rat spermatozoa were produced in mouse←rat ES chimeras. Rat spermatozoa from the chimeric testis were able to fertilize eggs by testicular sperm extraction combined with intracytoplasmic sperm injection (TESE-ICSI). In the present paper, we disrupted rat hypoxanthine-guanine phosphoribosyl transferase (Hprt) gene in ES cells and produced a Hprt-disrupted rat line using the mouse←rat ES chimera system. The mouse←rat ES chimera system demonstrated the dual advantages of space conservation and a clear indication of germ line transmission in knockout rat production. The investigation of gene functions has intensified following completion of genome projects in many species. A significant number of gene disrupted mouse lines have been produced using ES cells and the homologous recom- bination technique, for example, helping clarify the basic biology while serving as animal models for human diseases1. As a result, mice have replaced rats as the most popularly used experimental animal. However, rats retain advantages over mice as experimental animals2,3. Their bigger body size facilitates exper- imental operations and repeated collection of blood samples.
    [Show full text]
  • A Critical Role for the Type I Interferon Receptor in Virus-Induced Autoimmune Diabetes in Rats
    Diabetes Volume 66, January 2017 145 Natasha Qaisar,1 Suvana Lin,1 Glennice Ryan,1 Chaoxing Yang,2 Sarah R. Oikemus,3 Michael H. Brodsky,3 Rita Bortell,2 John P. Mordes,1 and Jennifer P. Wang1 A Critical Role for the Type I Interferon Receptor in Virus-Induced Autoimmune Diabetes in Rats Diabetes 2017;66:145–157 | DOI: 10.2337/db16-0462 The pathogenesis of human type 1 diabetes, character- is heritable but non-Mendelian, and genetic susceptibility loci ized by immune-mediated damage of insulin-producing are insufficient for predicting diabetes onset; most people b-cells of pancreatic islets, may involve viral infection. with risk alleles never become diabetic (2). Interaction of Essential components of the innate immune antiviral genes with environmental factors has been invoked as a response, including type I interferon (IFN) and IFN determinant of disease (3,4). Viral infection, particularly receptor–mediated signaling pathways, are candidates with enterovirus, is believed to be a key environmental mod- for determining susceptibility to human type 1 diabetes. Nu- ulator of T1D, and its possible role in pathogenesis has been PATHOPHYSIOLOGY merous aspects of human type 1 diabetes pathogenesis reviewed in detail (5,6). The mechanisms that underlie viral are recapitulated in the LEW.1WR1 rat model. Diabetes triggering of T1D remain unclear; b-cell infection, by- can be induced in LEW.1WR1 weanling rats challenged stander activation, antigenic spreading, and molecular with virus or with the viral mimetic polyinosinic:polycyti- mimicry have been proposed. Alternatively, viruses could dylic acid (poly I:C). We hypothesized that disrupting prevent T1D through immunoregulation or induction of thecognatetypeIIFNreceptor(typeIIFNa/b receptor [IFNAR]) to interrupt IFN signaling would prevent or delay protective immunity (7).
    [Show full text]
  • Survival Rates of Homozygotic Tp53 Knockout Rats As a Tool For
    Strzemecki et al. Cellular & Molecular Biology Letters (2017) 22:9 Cellular & Molecular DOI 10.1186/s11658-017-0039-z Biology Letters SHORTREPORT Open Access Survival rates of homozygotic Tp53 knockout rats as a tool for preclinical assessment of cancer prevention and treatment Damian Strzemecki†, Magdalena Guzowska† and Paweł Grieb* * Correspondence: [email protected] Abstract † Equal contributors Tp53 Department of Experimental Background: The gene that encodes tumor protein p53, , is mutated or Pharmacology, Mossakowski silenced in most human cancers and is recognized as one of the most important Medical Research Centre, Polish cancer drivers. Homozygotic Tp53 knockout mice, which develop lethal cancers early Academy of Sciences, 5 Tp Pawińskiego Str., Warsaw 02-106, in their lives, are already used in cancer prevention studies, and now 53 knockout Poland rats have also been generated. This study assessed feasibility of using homozygous Tp53 knockout rats to evaluate the possible outcome of cancer chemoprevention. Methods: A small colony of Tp53 knockout rats with a Wistar strain genetic background was initiated and maintained in the animal house at our institution. Tp53 heterozygotic females were bred with Tp53 homozygous knockout males to obtain a surplus of knockout homozygotes. To evaluate the reproducibility of their lifespan, 4 groups of Tp53 homozygous knockout male rats born during consecutive quarters of the year were kept behind a sanitary barrier in a controlled environment until they reached a moribund state. Their individual lifespan data were used to construct quarterly survival curves. Results: The four consecutive quarterly survival curves were highly reproducible. They were combined into a single “master” curve for use as a reference in intervention studies.
    [Show full text]
  • BCRP Knockout Rat
    Genetically engineered models (GEMS) BCRP knockout rat Model BCRP knockout rat Description Strain HsdSage: SD-Abcg2tm1Sage BCRP plays a protective role in neurotoxicity by limiting the efflux of xenobiotics into the brain. Homozygous null rats demonstrate Location U.S. increased exposure in the brain and plasma when dosed with Availability Live colony BCRP-specific substrates. Loss of function of Bcrp leads to improper transport of drugs across epithelial cells and increased bioavailability of Bcrp substrates. This model is useful for studying Characteristics/husbandry metabolism of xenobiotic compounds, tissue distribution, DMPK, efficacy, formulation, and blood brain barrier efflux. + Background strain: Sprague Dawley + Biallelic 588 bp deletion within Abcg2 gene Citations Homozygous knockouts display total loss of protein + 25868844 Bridges CC, Zalups RK, Joshee L. Toxicological significance of renal Bcrp: via Western blot Another potential transporter in the elimination of mercuric ions from proximal tubular cells. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):110-7. Increased oral bioavailability of BCRP-specific substrates + 25053619 Fuchs H, Kishimoto W, Gansser D, Tanswell P, Ishiguro N. Brain penetration of WEB 2086 (Apafant) and dantrolene in Mdr1a (P-glycoprotein) and Bcrp knockout rats. Drug Metab Dispos. 2014 Oct;42(10):1761-5. Zygosity genotype 29674491 Ganguly S, Panetta JC, Roberts JK, Schuetz EG. Ketamine Pharmacokinetics and Pharmacodynamics Are Altered by P-Glycoprotein and Breast Cancer Resistance + Homozygous Protein Efflux Transporters in Mice. Drug Metab Dispos. 2018 Jul;46(7):1014-1022 25539457 Huang L, Li X, Roberts J, Janosky B, Lin MH. Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF Research use and peripheral nerve tissues in rats.
    [Show full text]
  • Researchers Create First Targeted Knockout Rats Using Zinc Finger Nuclease Technology 23 July 2009
    Researchers create first targeted knockout rats using zinc finger nuclease technology 23 July 2009 Scientists from The Medical College of Wisconsin than are mice for many traits and are ideal subjects in Milwaukee, Sangamo Biosciences, Inc., Sigma- for modeling human diseases. Extensive genetic Aldrich Corporation, Open Monoclonal Technology, characterization has revealed that approximately 90 Inc. (OMT) and INSERM today announced the percent of the rat's 25,000-30,000 estimated genes creation of the first genetically modified mammals are analogous to those in humans and mice, and developed using zinc finger nuclease (ZFN) their larger size makes them a superior model for technology. drug-evaluation studies using serial sampling. Generating rats with knockout mutations has been In a paper published in the July 24, 2009 issue of a major challenge, but the new technique will Science, researchers describe the novel increase the rat's usefulness in research pertaining application of ZFNs to generate rats with to physiology, endocrinology, neurology, permanent, heritable gene mutations, paving the metabolism, parasitology, growth and development way for the development of novel genetically and cancer. Along with his colleagues, Dr. Jacob's modified animal models of human disease. ZFN team hopes to use knockout rats to gain a better technology will make the generation of such understanding of disease processes related to animals faster and will create new opportunities in hypertension, heart disease, kidney failure and species other than mice. cancer. "Until now, rat geneticists lacked a viable ZFNs are engineered proteins that induce double technique for "knocking out," or mutating, specific strand breaks at specific sites in an organism's genes to understand their function," said Howard DNA.
    [Show full text]
  • Oral Sessions
    FRIDAY, APRIL 1 Biochemistry and Molecular Biology 1. ASBMB GRADUATE AND POSTDOCTORAL TRAVEL AWARD PROFESSIONAL NETWORKING EVENT Special Event FRI. 5:30 PM— SAN DIEGO CONVENTION CENTER, ROOM 6A FOYER COCHAIRED: C. HEINEN AND T. O’CONNELL Invitation only. Required participation by all Graduate/ Postdoctoral and Graduate Student MAC Supported Travel Award recipients. Follow the conversation: #education Nutrition 2. ASN SPONSORED SATELLITE PROGRAM: 4. ASN CAROTENOID AND RETINOID A GLOBAL APPROACH TO PERSONALIZED INTERACTIVE GROUP (CARIG) ANNUAL NUTRITION FROM THE GENOME TO THE SYMPOSIUM AND BUSINESS MEETING MICROBIOME Special Event ASN Satellite (Sponsored by: CARIG RIS) (Organized and Sponsored by: Herbalife) FRI. 1:00 PM— HILTON SAN DIEGO BAYFRONT, AQUA AB FRI. 8:00 AM—HILTON SAN DIEGO BAYFRONT, INDIGO D CHAIRED: S.A. TANUMIHARDJO CHAIRED: D. HEBER Reception and CARIG Poster Competition to follow in Aqua C Visit the Exhibits April 3–April 5 Exhibit Hours Sunday – Tuesday 9:00 AM – 4:00 PM 1 SATURDAY, APRIL 2 Across Societies 5. CAREER DEVELOPMENT WORKSHOPS 10:00 Negotiation Strategies for Scientists Part 1. D. Behrens. Univ. of California, Berkeley. Workshop 10:30 Understanding Search Committees & Finding Job Announcements. A. Green. Univ. of SAT. 9:00 AM— SAN DIEGO CONVENTION CENTER, EXHIBIT HALL D California, Berkeley. Career Development 11:00 But I Have No Skills!. J. Lombardo. Med. Col. of Wisconsin and Marquette Univ. The following workshops will be held in the EB2016/FASEB 11:00 Beyond the Bench: Preparing for Your Career Transition Career Center. Access to the Career Center is FREE to all in the Life Sciences. J. Tringali.
    [Show full text]
  • Plenary Symposia
    In Vitro Cell.Dev.Biol.—Animal DOI 10.1007/s11626-014-9773-y 2014 WORLD FORUM ON BIOLOGY ABSTRACT ISSUE Plenary Symposia PS-1 and over-fishing on reefs, as well as, the increased warming and acidification of our seas. Regardless of this ominous Biotic Responses to Climate Change in the Antarctic Dry future, our laboratory holds out hope for these amazing places Valleys. D. H. WALL 1 and B. J. Adams2. 1School of Global on earth by creating germplasm banks for many its inhabi- Environmental Sustainability and Department of Biology, tants. To date, we have banked the sperm and embryonic stem Colorado State University, Fort Collins, CO 80523 cells of over 9 species of Australian, Caribbean and Hawaiian and2Department of Biology, and Evolutionary Ecology Lab- coral. We have thawed and created new coral from these oratories, Brigham Young University, Provo, UT 84602. frozen cells. This banked material can now be used to diver- Email: [email protected] sify areas where coral populations are shrinking. In addition to coral, however, we are establishing preservation protocols for Antarctica is a cold desert with less than 2% of the continent many other reef inhabitants. Recently, we cryopreserved the ice-free.Thelargesticefreeareasonthecontinent,the symbiotic algae living inside coral. These algal cells may be McMurdo Dry Valleys, are composed of soils, glaciers, lakes an important key for understanding and helping coral survive and meltstreams. This terrestrial ecosystem has no vascular stress. We are also cryopreserving the testicular cells of reef plants or animals above ground, but within different soil fish, such as gobies.
    [Show full text]