Mechanisms of normal and abnormal platelet homeostasis

描述（由申请人提供）：血栓性疾病是临床医学中最常见的疾病之一，也是美国发病率和死亡率的主要原因。血小板在这些疾病的发病机制中起着至关重要的作用，因为血小板聚集是导致血管闭塞事件的原因，而血管闭塞事件是这些疾病临床过程的关键。因此，本次SCCOR在止血和血栓形成方面的重点，题为“血小板正常和异常稳态的机制”，是血小板生物学的相关临床和基础方面，利用宾夕法尼亚大学研究人员在这些研究领域的丰富经验。SCCOR由3个临床和3个基础研究项目以及2个支持核心单位组成。项目1“了解肝素诱导的血小板减少症（HIT）的机制基础”，验证了血小板因子4 （PF4）分泌的变化是HIT发病率和临床表现不同的原因。项目2，题为“免疫介导的血小板减少症的免疫生物学”，研究ITP、HIT和TTP患者自身抗体反应的性质。项目3，题为“阿司匹林和氯吡格雷耐药的临床方面”，解决了“阿司匹林耐药”表型的稳定性、特异性和发生率，定义了阿司匹林耐药的新的脂质组学和蛋白质组学特征，并将传统的和新的生物标志物与临床结果联系起来。项目4名为“pleckstrin在血小板活化中的作用”，主要研究磷脂介导的信号通路及其在血小板和其他造血细胞的信号传导中所起的作用。项目5题为“Sema4D/CD100及其受体在血小板生物学和血栓形成中的作用”，研究血小板Sema4D/CD100及其受体在血小板功能中的作用，并测试可溶性Sema4D/CD100作为血栓形成事件的生物标志物的使用。项目6“血小板整合素功能调控”继续研究整合素激活状态的构象变化，重点研究血小板纤维蛋白原受体allb- β -3。这些项目由一个生物信息学核心来存储和分析临床数据，以及一个管理核心来支持。

DESCRIPTION (provided by applicant): 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.