Thrombotic disorders are among the most common diseases encountered in clinical medicine and are the leading causes of morbidity and mortality in the United States. Platelets play an essential role in the pathogenesis of these diseases because platelet aggregates are responsible for the vaso-occulsive events that puncuate their clinical course. Thus, the focus of this SCCOR in Hemostasis and Thrombosis, entitled """"""""Mechanisms of Normal and Abnormal Platelet Homeostasis"""""""", is on related clinical and basic aspects of platelet biology, taking advantage of the extensive experience of investigators at the University of Pennsylvania in these areas of investigation. The SCCOR consists of 3 clinical and 3 basic research projects, plus 2 supporting core units. Project 1, entitled """"""""Understanding the mechanistic basis of heparin-induced thrombocytopenia (HIT)"""""""", tests the hypothesis that variations in platelet factor 4 (PF4) secretion are responsible for the variable incidence and clinical manifestations of HIT. Project 2, entitled """"""""Immunobiology of immune-mediated thrombocytopenias"""""""" studies the nature of autoantibody responses in patients with ITP, HIT, and TTP. Project 3, entitled """"""""Clinical aspects of aspirin and clopidogrel resistance"""""""", addresses the stability, specificity and incidence of the """"""""aspirin resistant"""""""" phenotype, defines novel lipidomic and proteomic signatures of aspirin resistance, and relates conventional and novel biomarkers of the phenotype to clinical outcome. Project 4, entitled """"""""Role of pleckstrin in platelet activation"""""""", is focused on phospholipid-mediated signaling pathways and the role they play in signaling in platelets and other cells of hematopoietic origin. Project 5, entitled """"""""The role of Sema4D/CD100 and its receptors in platelet biology and thrombosis"""""""", studies the role of platelet sema4D/CD100 and its receptors in platelet function and tests the use of soluble sema4D/CD100 as a biomarker for thrombotic events. Project 6, entitled """"""""Regulation of platelet integrin function"""""""", continues to study the conformational changes that regulate integrin activation states, focusing on the platelet fibrinogen receptor allb-beta-3. The projects are supported by a Bioinformatics Core to store and analyze clinical data and by a Core for Administration.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL081012-05
Application #
7808883
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S1))
Program Officer
Link, Rebecca P
Project Start
2006-03-27
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$2,477,520
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ostertag, Eric M; Kacir, Stephen; Thiboutot, Michelle et al. (2016) ADAMTS13 autoantibodies cloned from patients with acquired thrombotic thrombocytopenic purpura: 1. Structural and functional characterization in vitro. Transfusion 56:1763-74
Ostertag, Eric M; Bdeir, Khalil; Kacir, Stephen et al. (2016) ADAMTS13 autoantibodies cloned from patients with acquired thrombotic thrombocytopenic purpura: 2. Pathogenicity in an animal model. Transfusion 56:1775-85
Casina, Veronica C; Hu, Wenbing; Mao, Jian-Hua et al. (2015) High-resolution epitope mapping by HX MS reveals the pathogenic mechanism and a possible therapy for autoimmune TTP syndrome. Proc Natl Acad Sci U S A 112:9620-5
Lu, Qiongyu; Dong, Ningzheng; Wang, Qi et al. (2013) Increased levels of plasma soluble Sema4D in patients with heart failure. PLoS One 8:e64265
Wannemacher, K M; Jiang, H; Hess, P R et al. (2013) An expanded role for semaphorin 4D in platelets includes contact-dependent amplification of Clec-2 signaling. J Thromb Haemost 11:2190-3
Mou, Peipei; Zeng, Zhao; Li, Qiang et al. (2013) Identification of a calmodulin-binding domain in Sema4D that regulates its exodomain shedding in platelets. Blood 121:4221-30
Moore, David T; Nygren, Patrik; Jo, Hyunil et al. (2012) Affinity of talin-1 for the ?3-integrin cytosolic domain is modulated by its phospholipid bilayer environment. Proc Natl Acad Sci U S A 109:793-8
Sun, Jessie E P; Vranic, Justin; Composto, Russell J et al. (2012) Bimolecular integrin-ligand interactions quantified using peptide-functionalized dextran-coated microparticles. Integr Biol (Camb) 4:84-92
Litvinov, Rustem I; Mekler, Andrey; Shuman, Henry et al. (2012) Resolving two-dimensional kinetics of the integrin ?IIb?3-fibrinogen interactions using binding-unbinding correlation spectroscopy. J Biol Chem 287:35275-85
Litvinov, Rustem I; Barsegov, Valeri; Schissler, Andrew J et al. (2011) Dissociation of bimolecular ?IIb?3-fibrinogen complex under a constant tensile force. Biophys J 100:165-73

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