Studies of Physiologic and Pathologic Platelet Plug Formation

计划简介摘要： 这是我们重新命名的新计划项目(HL146373-01)的重新提交 《生理学和病理性血小板凝块形成研究》更准确地反映 计划项目涉及的主题。除了在部位形成止血塞外 血管损伤，血小板在炎症等过程中起重要作用， 组织再生、宿主防御、血管生成、淋巴管发展和肿瘤转移。 病理性血小板血栓也是导致心力衰竭的主要原因。 动脉血管疾病。在我们对生理学和生理学的理解上仍有很大差距 病理性血小板功能。在我们集体科学成就的基础上，我们解决 这些缺口使用细胞生物学、结构生物学和计算生物学方法，我们 已经发展起来了。我们提出的计划项目包括四个项目和一个 行政核心单位。所有的项目都设在佩雷尔曼医学院 宾夕法尼亚大学。有三个项目设在北京的血液肿瘤科 医学系；第四个设在美国国家卫生研究院血液科 费城儿童医院儿科。项目1，改名为“小说” 磷脂酰肌醇信号转导在α-颗粒生物发生中的作用“，是基于假设 磷脂酰肌醇的合成是α颗粒载药的关键步骤 合成在高尔基体中的巨核细胞磷脂酰肌醇 在先天性巨核细胞疾病的发展中所起的未被认识的作用。的目标 题为《血小板整合素结构和功能》的项目2将使用新的计算和 比较αIIbβ3与其他整合素和 鉴定和量化导致αIIbβ3介导的纤维蛋白凝块的蛋白质-蛋白质相互作用 收缩。项目3题为“止血和血栓形成的系统方法”。这个 本项目提出的研究目标是扩展过去对血小板血栓的分析 从微血管到大血管的形成和结构，从小鼠到 从止血到血栓形成。项目4，题为“血小板第4因子和肝素” 在网状肺炎和败血症中，将检验这样一种假设，即Net，中性粒细胞胞外陷阱 由中性粒细胞释放的染色质组成，需要部分消化和释放DNA 而组蛋白在脓毒症期间是有毒的。因为输注的血小板因子4，以及 结合血小板第4因子和肝素复合体的单抗Kko，阻断DNA 消化，两者对脓毒症都有保护作用。这四个项目由一个核心单位提供支持 这就满足了该方案的共同管理需要。

PROGRAM INTRODUCTION SUMMARY: This is the re-submission of a new Program Project (HL146373-01) that we have re-named “Studies of Physiologic and Pathologic Platelet Plug Formation” to more accurately reflect the topics the Program Project addresses. In addition to forming hemostatic plugs at sites of vascular injury, platelets make important contributions to processes such as inflammation, tissue regeneration, host defense, angiogenesis, lymphatic development, and tumor metastasis. Pathologic platelet thrombi are also responsible for much of the morbidity and mortality of arterial vascular disease. There remain large gaps in our understanding of physiologic and pathologic platelet function. Building upon our collective scientific accomplishments, we address these gaps using the cell-biologic, structural-biologic, and computational-biologic methods we have developed. The Program Project we propose consists of four projects and one administrative core unit. All of the projects are based at the Perelman School of Medicine of the University of Pennsylvania. Three projects are based in the Hematology-Oncology Division of the Department of Medicine; the fourth is based in the Division of Hematology of the Department of Pediatrics at The Children's Hospital of Philadelphia. Project 1, re-named “Novel Roles for Phosphoinositide Signaling in α-Granule Biogenesis”, is based on the hypotheses that phosphoinositide synthesis is an essential step in the loading of α-granules with components synthesized in the Golgi and that megakaryocyte phosphoinositides play a previously unrecognized role in the development of congenital megakaryocyte disorders. The objectives of Project 2, entitled “Platelet Integrin Structure and Function”, are to use novel computational and experimental techniques to compare the behavior of αIIbβ3 with that of the other integrins and to identify and quantify the protein-protein interactions responsible for αIIbβ3-mediated fibrin clot contraction. Project 3 is entitled “A Systems Approach to Hemostasis and Thrombosis“. The goals of the studies proposed in this Project are to extend past analyses of platelet thrombus formation and structure from the microvasculature to the macrovasculature, from mice to humans, and from hemostasis to thrombosis. Project 4, entitled “Platelet Factor 4 and Heparin in NETosis and Sepsis”, will test the hypothesis that NETs, neutrophil extracellular traps composed of chromatin released by neutrophils, require partial digestion and release of DNA and histones to be toxic during sepsis. Because infused platelet factor 4, as well as the monoclonal antibody KKO that binds to the complex of platelet factor 4 and heparin, block DNA digestion, both will be protective in sepsis. The four projects are supported by a single core unit that provides for the common administrative needs of the Program.