DOCSLIB.ORG

Genetic Architecture of Host Proteins Involved in SARS-Cov-2 Infection

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic Architecture of Host Proteins Involved in SARS-Cov-2 Infection ARTICLE https://doi.org/10.1038/s41467-020-19996-z OPEN Genetic architecture of host proteins involved in SARS-CoV-2 infection Maik Pietzner1, Eleanor Wheeler 1, Julia Carrasco-Zanini1, Johannes Raffler 2, Nicola D. Kerrison1, Erin Oerton1, Victoria P. W. Auyeung 1, Jian’an Luan 1, Chris Finan 3,4, Juan P. Casas5,6, Rachel Ostroff7, Steve A. Williams 7, Gabi Kastenmüller 2, Markus Ralser8,9, Eric R. Gamazon 1,10, ✉ ✉ Nicholas J. Wareham 1,11, Aroon D. Hingorani 3,4,12 & Claudia Langenberg 1,8,11,13 1234567890():,; Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or med- iating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phe- nome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver (https://omicscience.org/apps/covidpgwas/). 1 MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. 2 Institute of Computational Biology, Helmholtz Zentrum München – German Research Center for Environmental Health, Neuherberg, Germany. 3 Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London WC1E 6BT, UK. 4 UCL BHF Research Accelerator centre, London, UK. 5 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 6 Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA. 7 SomaLogic, Inc., Boulder, CO, USA. 8 The Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, London, UK. 9 Department of Biochemistry, Charité University Medicine, Berlin, Germany. 10 Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. 11 Health Data Research UK, Wellcome Genome Campus and University of Cambridge, Cambridge, UK. 12 Health Data Research UK, Institute of Health Informatics, University College London, London, UK. 13 Computational Medicine, Berlin Institute of Health (BIH), Charité University ✉ Medicine, Berlin, Germany. email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2020) 11:6397 | https://doi.org/10.1038/s41467-020-19996-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19996-z he pandemic of the novel coronavirus SARS-CoV-2 example, if confirmed, the reported protective effect of blood infection, the cause of COVID-19, is causing severe glo- group O on COVID-19-induced respiratory failure10 might well T 1,2 bal disruption and excess mortality . While ultimately be mediated by the effect of genetically reduced activity of an strategies are required that create vaccine-derived population ubiquitously expressed glycosyltransferase on a diverse range of immunity, in the medium term there is a need to develop new proteins. therapies or to repurpose existing drugs that are effective in In this study, we integrate large-scale genomic and aptamer- treating patients with severe complications of COVID-19, and based plasma proteomic data from a population-based study of also to identify agents that might protect vulnerable individuals 10,708 individuals prior to any SARS-CoV-2 infection or from becoming infected. The experimental characterization of COVID-19 to characterize the genetic architecture of 179 host 332 SARS-CoV-2-human protein–protein interactions and their proteins relevant to COVID-19. We identify genetic variants that mapping to 69 existing FDA-approved drugs, drugs in clinical regulate host proteins interacting with SARS-CoV-2, or which trials, and/or preclinical compounds3 points to new therapeutic may contribute to the maladaptive host response. We deeply strategies, some of which are currently being tested. The mea- characterize protein quantitative trait loci (pQTLs) in close surement of circulating host proteins that associate with COVID- proximity to protein-encoding genes (±500 kb window around 19 severity or mortality also provides insight into potentially the gene body), cis-pQTLs, and use genetic score analysis and targetable maladaptive host responses with current interest being phenome-wide scans to interrogate potential consequences for focused on the innate immune response4, coagulation5,6, and targeting those proteins by drugs. Our results enable the use of novel candidate proteins7. genetic variants as instruments for drug target validation in Naturally occurring sequence variation in or near a human emerging genome-wide association studies (GWAS) of SARS- gene that is encoding a drug target and affecting its expression or CoV-2 infection and COVID-1910,11. activity can be used to provide direct support for drug mechan- isms and safety in humans. This approach is now used by major pharmaceutical companies for drug target identification and Results validation for a wide range of non-communicable diseases, and to Coverage of COVID-19-relevant proteins. We identified guide drug repurposing8,9. Genetic evidence linking molecular COVID-19-relevant candidate proteins based on different layers targets to diseases relies on our understanding of the genetic of evidence to be involved in the pathology of COVID-19: (1) two architecture of drug targets. Proteins are the most common human proteins related to viral entry12, (2) 332 human proteins biological class of drug targets and advances in high-throughput shown to interact with viral proteins3, (3) 26 proteomic markers proteomic technologies have enabled systematic analysis of the of disease severity7, and (4) 54 protein biomarkers of adverse “human druggable proteome” and genetic target validation to prognosis, complications, and disease deterioration4–6,13 (Fig. 1 rapidly accelerate the prioritization (or de-prioritization) of and Supplementary Data 1). Of the 409 proteins prioritized, 179 therapeutic targets for new drug development or repurposing were detectable by the currently most-comprehensive proteomic trials. assay using an aptamer-based technology (SomaScan©), including Identification and in-depth genetic characterization of proteins 28 recognized by more than one aptamer (i.e., 179 proteins utilized by SARS-CoV-2 for entry and replication as well as those recognized by 190 aptamers). We further included com- proteins involved in the maladaptive host response will help to plementary data from proximity extensions assays (Olink©) for understand the systemic consequences of COVID-19. For 32 out of the 179 candidate proteins in a subset of 485 Fenland 2 Proteins for viral entry 332 Proteins identified as interaction partners withSARS-CoV-2 409 Candidate 4,775 Proteins measured 26 Proteins associated with disease proteins using SOMAscan v4 severity 54 Clinical biomarkers of outcome and prognosis 179 Candidate proteins measured among 10,708 participants of the Fenland study with available genotype data 50 SOMAscan v4 Covered 40 Not covered 30 20 # Proteins 10 0 E N M orf6 orf8 nsp1 nsp2 nsp4 nsp5 nsp6 nsp7 nsp8 nsp9 orf9c orf3a orf3b orf7a orf9b orf10 Spike nsp10 nsp11 nsp12 nsp13 nsp14 nsp15 Virus entry Fibrinolysis nsp5_C145A Cytokine storm Disease severity Viral baits Adverse prognosis Coagualtion cascade Fig. 1 Flowchart of the identification of candidate proteins and coverage by the SomaScan v4 platform within the Fenland cohort. More details for each protein targeted are given in Supplementary Data 1. 2 NATURE COMMUNICATIONS | (2020) 11:6397 | https://doi.org/10.1038/s41467-020-19996-z | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19996-z ARTICLE Chromosomal position 12345678 9 10 11 12 13 14 15 16 17 18 19 20 22 X 4000 100 -value) p 50 –log10( 0 F8 F5 F7 C2 TF F9* F2* F11 IDE HP* LBP C1S GLA CFB AES C1R C8G C8G CFH IL7R IL6R CRP FGG F10* POR | CKM FGG* VWF GGH ITIH4 ETFA PLG* F13B F13B | ITIH3 PPT1 | PLAT PLD3 C1RL SAA1 SDF2 PKP2 SAA2 GSN* GPX1 IL1R1 | IL1R2 IL2RA VWA1 IL6ST IL2RB VWA2 IL1RN PROC CD14* COMT AP2A2 FBLN5 NPTX1 IL1RL1 RAB2A RAB1A FKBP7 IL1RL2 GDF15 APOA1 IL17RA ElF4E2 PLOD2 PROS1 LMAN2 QSOX2 MFGE8 HMOX1 MARK3 IL1RAP SMOC1 ACADM SVEP1* COL6A1 ERLEC1 DCTPP1 POFUT1 GRPEL1 KDELC2 PTGES2 IGHG1-4 ERO1LB SCARA5 C8B FAM162A FGB | | CKB SEPSECS SERPINE1 SERPINC1 COLGALT1 LGALS3BP RAP1GDS1 SERPINA10 F13A1 FGA C8A Virus entry SARS-CoV2-Human PPl Disease severity Adverse prognosis Coagulation cascade Fibrinolysis Cytokine storm Fig. 2 Manhattan plot of cis-associations statistics (encoding gene ±500 kb) for 179 proteins. The most significant regional sentinel protein quantitative trait loci (pQTL) acting in cis are annotated by larger dots for 104 unique protein targets (dashed line; p <5×10−8). Starred genes indicate those targeted by multiple aptamers (n = 9 genes). study individuals (Supplementary Data 1). Of these 179 proteins, targets,
Load more

Recommended publications
  • Genetics of Interleukin 1 Receptor-Like 1 in Immune and Inflammatory Diseases
    Current Genomics, 2010, 11, 591-606 591 Genetics of Interleukin 1 Receptor-Like 1 in Immune and Inflammatory Diseases Loubna Akhabir and Andrew Sandford* Department of Medicine, University of British Columbia, UBC James Hogg Research Centre, Providence Heart + Lung Institute, Room 166, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada Abstract: Interleukin 1 receptor-like 1 (IL1RL1) is gaining in recognition due to its involvement in immune/inflamma- tory disorders. Well-designed animal studies have shown its critical role in experimental allergic inflammation and human in vitro studies have consistently demonstrated its up-regulation in several conditions such as asthma and rheumatoid ar- thritis. The ligand for IL1RL1 is IL33 which emerged as playing an important role in initiating eosinophilic inflammation and activating other immune cells resulting in an allergic phenotype. An IL1RL1 single nucleotide polymorphism (SNP) was among the most significant results of a genome-wide scan inves- tigating eosinophil counts; in the same study, this SNP associated with asthma in 10 populations. The IL1RL1 gene resides in a region of high linkage disequilibrium containing interleukin 1 receptor genes as well as in- terleukin 18 receptor and accessory genes. This poses a challenge to researchers interested in deciphering genetic associa- tion signals in the region as all of the genes represent interesting candidates for asthma and allergic disease. The IL1RL1 gene and its resulting soluble and receptor proteins have emerged as key regulators of the inflammatory proc- ess implicated in a large variety of human pathologies We review the function and expression of the IL1RL1 gene.
    [Show full text]
  • The Development of Asthma and Atopy Reijmerink, Naomi Elizabeth
    University of Groningen A search for missing pieces of the puzzle; the development of asthma and atopy Reijmerink, Naomi Elizabeth IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2009 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Reijmerink, N. E. (2009). A search for missing pieces of the puzzle; the development of asthma and atopy: innate immunity genes and environment. [s.n.]. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 26-09-2021 Chapter 3 Association of IL1RL1, IL18R1 and IL18RAP gene cluster polymorphisms with asthma and atopy Naomi E. Reijmerink Dirkje S. Postma Marcel Bruinenberg Ilja M. Nolte Deborah A. Meyers Eugene R. Bleecker Gerard H. Koppelman J Allergy Clin Immunol. 2008 Sep;122(3):651-4.
    [Show full text]
  • Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug
    cancers Article Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia David G.J. Cucchi 1 , Costa Bachas 1 , Marry M. van den Heuvel-Eibrink 2,3, Susan T.C.J.M. Arentsen-Peters 3, Zinia J. Kwidama 1, Gerrit J. Schuurhuis 1, Yehuda G. Assaraf 4, Valérie de Haas 3 , Gertjan J.L. Kaspers 3,5 and Jacqueline Cloos 1,* 1 Hematology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected] (D.G.J.C.); [email protected] (C.B.); [email protected] (Z.J.K.); [email protected] (G.J.S.) 2 Department of Pediatric Oncology/Hematology, Erasmus MC–Sophia Children’s Hospital, 3015 CN Rotterdam, The Netherlands; [email protected] 3 Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; [email protected] (S.T.C.J.M.A.-P.); [email protected] (V.d.H.); [email protected] (G.J.L.K.) 4 The Fred Wyszkowski Cancer Research, Laboratory, Department of Biology, Technion-Israel Institute of Technology, 3200003 Haifa, Israel; [email protected] 5 Emma’s Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands * Correspondence: [email protected] Received: 21 April 2020; Accepted: 12 May 2020; Published: 15 May 2020 Abstract: Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization.
    [Show full text]
  • CD4 T-Cell Cytokines Synergize to Induce Proliferation of Malignant and Nonmalignant Innate Intraepithelial Lymphocytes
    CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes Yvonne M. C. Kooy-Winkelaara, Dagmar Bouwera, George M. C. Janssenb, Allan Thompsona, Martijn H. Brugmana, Frederike Schmitza, Arnoud H. de Rub, Tom van Gilsc, Gerd Boumac, Jon J. van Rooda,1, Peter A. van Veelenb, M. Luisa Mearind, Chris J. Mulderc, Frits Koninga, and Jeroen van Bergena,1 aDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands; bCenter for Proteomics and Metabolomics, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands; cDepartment of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam 1081 HZ, The Netherlands; and dDepartment of Pediatrics, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands Contributed by Jon J. van Rood, December 7, 2016 (sent for review January 6, 2016; reviewed by Georg Gasteiger and Bana Jabri) − Refractory celiac disease type II (RCDII) is a severe complication of lymphoma, because the Lin IELs expanded in RCDII often give celiac disease (CD) characterized by the presence of an enlarged rise to type I enteropathy-associated T-cell lymphoma (EATL). − clonal population of innate intraepithelial lymphocytes (IELs) lacking The main treatment goal in RCDII is to eliminate the Lin IEL − classical B-, T-, and natural killer (NK)-cell lineage markers (Lin IELs) population before its transformation into a high-grade lymphoma. in the duodenum. In ∼50% of patients with RCDII, these Lin−IELs Cladribine (2-CDA) is thought to be especially active against low- develop into a lymphoma for which no effective treatment is avail- grade malignancies with limited proliferative capacity, and reduces − able.
    [Show full text]
  • Dual Proteome-Scale Networks Reveal Cell-Specific Remodeling of the Human Interactome
    bioRxiv preprint doi: https://doi.org/10.1101/2020.01.19.905109; this version posted January 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Dual Proteome-scale Networks Reveal Cell-specific Remodeling of the Human Interactome Edward L. Huttlin1*, Raphael J. Bruckner1,3, Jose Navarrete-Perea1, Joe R. Cannon1,4, Kurt Baltier1,5, Fana Gebreab1, Melanie P. Gygi1, Alexandra Thornock1, Gabriela Zarraga1,6, Stanley Tam1,7, John Szpyt1, Alexandra Panov1, Hannah Parzen1,8, Sipei Fu1, Arvene Golbazi1, Eila Maenpaa1, Keegan Stricker1, Sanjukta Guha Thakurta1, Ramin Rad1, Joshua Pan2, David P. Nusinow1, Joao A. Paulo1, Devin K. Schweppe1, Laura Pontano Vaites1, J. Wade Harper1*, Steven P. Gygi1*# 1Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. 2Broad Institute, Cambridge, MA, 02142, USA. 3Present address: ICCB-Longwood Screening Facility, Harvard Medical School, Boston, MA, 02115, USA. 4Present address: Merck, West Point, PA, 19486, USA. 5Present address: IQ Proteomics, Cambridge, MA, 02139, USA. 6Present address: Vor Biopharma, Cambridge, MA, 02142, USA. 7Present address: Rubius Therapeutics, Cambridge, MA, 02139, USA. 8Present address: RPS North America, South Kingstown, RI, 02879, USA. *Correspondence: [email protected] (E.L.H.), [email protected] (J.W.H.), [email protected] (S.P.G.) #Lead Contact: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.01.19.905109; this version posted January 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
    [Show full text]
  • 1 Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental
    Page 1 of 255 Diabetes Metabolic dysfunction is restricted to the sciatic nerve in experimental diabetic neuropathy Oliver J. Freeman1,2, Richard D. Unwin2,3, Andrew W. Dowsey2,3, Paul Begley2,3, Sumia Ali1, Katherine A. Hollywood2,3, Nitin Rustogi2,3, Rasmus S. Petersen1, Warwick B. Dunn2,3†, Garth J.S. Cooper2,3,4,5* & Natalie J. Gardiner1* 1 Faculty of Life Sciences, University of Manchester, UK 2 Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK 3 Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, UK 4 School of Biological Sciences, University of Auckland, New Zealand 5 Department of Pharmacology, Medical Sciences Division, University of Oxford, UK † Present address: School of Biosciences, University of Birmingham, UK *Joint corresponding authors: Natalie J. Gardiner and Garth J.S. Cooper Email: [email protected]; [email protected] Address: University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, United Kingdom Telephone: +44 161 275 5768; +44 161 701 0240 Word count: 4,490 Number of tables: 1, Number of figures: 6 Running title: Metabolic dysfunction in diabetic neuropathy 1 Diabetes Publish Ahead of Print, published online October 15, 2015 Diabetes Page 2 of 255 Abstract High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However our understanding of the molecular mechanisms which cause the marked distal pathology is incomplete. Here we performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN.
    [Show full text]
  • Glucose-Induced Changes in Gene Expression in Human Pancreatic Islets: Causes Or Consequences of Chronic Hyperglycemia
    Diabetes Volume 66, December 2017 3013 Glucose-Induced Changes in Gene Expression in Human Pancreatic Islets: Causes or Consequences of Chronic Hyperglycemia Emilia Ottosson-Laakso,1 Ulrika Krus,1 Petter Storm,1 Rashmi B. Prasad,1 Nikolay Oskolkov,1 Emma Ahlqvist,1 João Fadista,2 Ola Hansson,1 Leif Groop,1,3 and Petter Vikman1 Diabetes 2017;66:3013–3028 | https://doi.org/10.2337/db17-0311 Dysregulation of gene expression in islets from patients In patients with type 2 diabetes (T2D), islet function de- with type 2 diabetes (T2D) might be causally involved clines progressively. Although the initial pathogenic trigger in the development of hyperglycemia, or it could develop of impaired b-cell function is still unknown, elevated glu- as a consequence of hyperglycemia (i.e., glucotoxicity). cose levels are known to further aggravate b-cell function, a To separate the genes that could be causally involved condition referred to as glucotoxicity, which can stimulate in pathogenesis from those likely to be secondary to hy- apoptosis and lead to reduced b-cell mass (1–5). Prolonged perglycemia, we exposed islets from human donors to exposure to hyperglycemia also can induce endoplasmic re- ISLET STUDIES normal or high glucose concentrations for 24 h and ana- ticulum (ER) stress and production of reactive oxygen spe- fi lyzed gene expression. We compared these ndings with cies (6), which can further impair islet function and thereby gene expression in islets from donors with normal glucose the ability of islets to secrete the insulin needed to meet the tolerance and hyperglycemia (including T2D). The genes increased demands imposed by insulin resistance and obe- whose expression changed in the same direction after sity (7).
    [Show full text]
  • Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle
    animals Article Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle Masoumeh Naserkheil 1 , Abolfazl Bahrami 1 , Deukhwan Lee 2,* and Hossein Mehrban 3 1 Department of Animal Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj 77871-31587, Iran; [email protected] (M.N.); [email protected] (A.B.) 2 Department of Animal Life and Environment Sciences, Hankyong National University, Jungang-ro 327, Anseong-si, Gyeonggi-do 17579, Korea 3 Department of Animal Science, Shahrekord University, Shahrekord 88186-34141, Iran; [email protected] * Correspondence: [email protected]; Tel.: +82-31-670-5091 Received: 25 August 2020; Accepted: 6 October 2020; Published: 9 October 2020 Simple Summary: Hanwoo is an indigenous cattle breed in Korea and popular for meat production owing to its rapid growth and high-quality meat. Its yearling weight and carcass traits (backfat thickness, carcass weight, eye muscle area, and marbling score) are economically important for the selection of young and proven bulls. In recent decades, the advent of high throughput genotyping technologies has made it possible to perform genome-wide association studies (GWAS) for the detection of genomic regions associated with traits of economic interest in different species. In this study, we conducted a weighted single-step genome-wide association study which combines all genotypes, phenotypes and pedigree data in one step (ssGBLUP). It allows for the use of all SNPs simultaneously along with all phenotypes from genotyped and ungenotyped animals. Our results revealed 33 relevant genomic regions related to the traits of interest.
    [Show full text]
  • MINIREVIEW Complex Role of Matrix Metalloproteinases in Angiogen- Esis
    Cell Research (1998), 8, 171-177 MINIREVIEW Complex role of matrix metalloproteinases in angiogen- esis SANG QING XIANG AMY* Biochemistry Division, Department of Chemistry, Florida State University, Tallahassee, Florida 32306-4390, USA ABSTRACT Matrix metalloproteinases (MMPs) and tissue in- hibitors of metalloproteinases (TIMPs) play a significant role in regulating angiogenesis, the process of new blood vessel formation. Interstitial collagenase (MMP-1), 72 kDa gelatinase A/type IV collagenase (MMP-2), and 92 kDa gelatinase B/type IV collagenase (MMP-9) dissolve ex- tracellular matrix (ECM) and may initiate and promote angiogenesis. TIMP-1, TIMP-2, TIMP-3, and possibly, TIMP-4 inhibit neovascularization. A new paradigm is emerging that matrilysin (MMP-7), MMP-9, and metal- loelastase (MMP-12) may block angiogenesis by convert- ing plasminogen to angiostatin, which is one of the most potent angiogenesis antagonists. MMPs and TIMPs play a complex role in regulating angiogenesis. An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide important information to al- low the control of angiogenesis, e.g. the stimulation of angiogenesis for coronary collateral circulation formation; while the inhibition for treating arthritis and cancer. Key word s: Collagenases, tissue inhibitors of metallo- proteinases, neovascularization, plasmino- gen angiostatin converting enzymes, ex- tracellular matrix. * Corresponding author: Professor Qing Xiang Amy Sang, Department of Chemistry, 203 Dittmer Laboratory of Chemistry Building, Florida State University, Tallahassee, Florida 32306-4390, USA Phone: (850) 644-8683 Fax: (850) 644-8281 E-mail: [email protected]. 171 MMPs in angiogenesis Significance of matrix metalloproteinases in angiogenesis Matrix metalloproteinases (MMPs) are a family of highly homologous zinc en- dopeptidases that cleave peptide bonds of the extracellular matrix (ECM) proteins, such as collagens, laminins, elastin, and fibronectin[1, 2, 3].
    [Show full text]
  • CD29 Identifies IFN-Γ–Producing Human CD8+ T Cells With
    + CD29 identifies IFN-γ–producing human CD8 T cells with an increased cytotoxic potential Benoît P. Nicoleta,b, Aurélie Guislaina,b, Floris P. J. van Alphenc, Raquel Gomez-Eerlandd, Ton N. M. Schumacherd, Maartje van den Biggelaarc,e, and Monika C. Wolkersa,b,1 aDepartment of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, The Netherlands; bLandsteiner Laboratory, Oncode Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; cDepartment of Research Facilities, Sanquin Research, 1066 CX Amsterdam, The Netherlands; dDivision of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and eDepartment of Molecular and Cellular Haemostasis, Sanquin Research, 1066 CX Amsterdam, The Netherlands Edited by Anjana Rao, La Jolla Institute for Allergy and Immunology, La Jolla, CA, and approved February 12, 2020 (received for review August 12, 2019) Cytotoxic CD8+ T cells can effectively kill target cells by producing therefore developed a protocol that allowed for efficient iso- cytokines, chemokines, and granzymes. Expression of these effector lation of RNA and protein from fluorescence-activated cell molecules is however highly divergent, and tools that identify and sorting (FACS)-sorted fixed T cells after intracellular cytokine + preselect CD8 T cells with a cytotoxic expression profile are lacking. staining. With this top-down approach, we performed an un- + Human CD8 T cells can be divided into IFN-γ– and IL-2–producing biased RNA-sequencing (RNA-seq) and mass spectrometry cells. Unbiased transcriptomics and proteomics analysis on cytokine- γ– – + + (MS) analyses on IFN- and IL-2 producing primary human producing fixed CD8 T cells revealed that IL-2 cells produce helper + + + CD8 Tcells.
    [Show full text]
  • Recombinant Human Angiostatin by Twice-Daily Subcutaneous Injection in Advanced Cancer: a Pharmacokinetic and Long-Term Safety Study1
    Vol. 9, 4025–4033, September 15, 2003 Clinical Cancer Research 4025 Recombinant Human Angiostatin by Twice-Daily Subcutaneous Injection in Advanced Cancer: A Pharmacokinetic and Long-Term Safety Study1 Laurens V. Beerepoot, Els O. Witteveen, patients went off study after developing hemorrhage in Gerard Groenewegen, William E. Fogler, brain metastases, and 2 patients developed deep venous B. Kim Leel Sim, Carolyn Sidor, thrombosis. No other relevant treatment-related toxicities were seen, even during prolonged treatment. A panel Bernard A. Zonnenberg, Franz Schramel, of coagulation parameters was not influenced by 2 Martijn F. B. G. Gebbink, and Emile E. Voest rhAngiostatin treatment. Long-term (>6 months) stable Department of Medical Oncology, University Medical Center Utrecht disease (<25% growth of measurable uni- or bidimen- 3508 GA, the Netherlands [L. V. B., P. O. W., G. G., B. A. Z., F. S., sional tumor size) was observed in 6 of 24 patients. Five M. F. B. G. G., E. E. V.], and EntreMed Inc., Rockville, Maryland patients received rhAngiostatin treatment for 1 year 20850 [W. E. F., B. K. L. S., C. S.] > (overall median time on treatment 99 days). Conclusions: Long-term twice-daily s.c. treatment ABSTRACT with rhAngiostatin is well tolerated and feasible at the Purpose: A clinical study was performed to evaluate selected doses, and merits additional evaluation. Sys- the pharmacokinetics (PK) and toxicity of three dose temic exposure to rhAngiostatin is within the range of levels of the angiogenesis inhibitor recombinant human drug exposure that has biological activity in preclinical (rh) angiostatin when administered twice daily by s.c.
    [Show full text]
  • The Plasmin–Antiplasmin System: Structural and Functional Aspects
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Bern Open Repository and Information System (BORIS) Cell. Mol. Life Sci. (2011) 68:785–801 DOI 10.1007/s00018-010-0566-5 Cellular and Molecular Life Sciences REVIEW The plasmin–antiplasmin system: structural and functional aspects Johann Schaller • Simon S. Gerber Received: 13 April 2010 / Revised: 3 September 2010 / Accepted: 12 October 2010 / Published online: 7 December 2010 Ó Springer Basel AG 2010 Abstract The plasmin–antiplasmin system plays a key Plasminogen activator inhibitors Á a2-Macroglobulin Á role in blood coagulation and fibrinolysis. Plasmin and Multidomain serine proteases a2-antiplasmin are primarily responsible for a controlled and regulated dissolution of the fibrin polymers into solu- Abbreviations ble fragments. However, besides plasmin(ogen) and A2PI a2-Antiplasmin, a2-Plasmin inhibitor a2-antiplasmin the system contains a series of specific CHO Carbohydrate activators and inhibitors. The main physiological activators EGF-like Epidermal growth factor-like of plasminogen are tissue-type plasminogen activator, FN1 Fibronectin type I which is mainly involved in the dissolution of the fibrin K Kringle polymers by plasmin, and urokinase-type plasminogen LBS Lysine binding site activator, which is primarily responsible for the generation LMW Low molecular weight of plasmin activity in the intercellular space. Both activa- a2M a2-Macroglobulin tors are multidomain serine proteases. Besides the main NTP N-terminal peptide of Pgn physiological inhibitor a2-antiplasmin, the plasmin–anti- PAI-1, -2 Plasminogen activator inhibitor 1, 2 plasmin system is also regulated by the general protease Pgn Plasminogen inhibitor a2-macroglobulin, a member of the protease Plm Plasmin inhibitor I39 family.
    [Show full text]