Studies of Physiologic and Pathologic Platelet Plug Formation

项目简介概要： 这是我们重新命名的新计划项目（HL146373-01）的重新提交 “生理和病理性血小板栓子形成的研究”更准确地反映 计划项目涉及的主题。除了在以下部位形成止血塞之外 血管损伤、血小板对炎症等过程做出重要贡献， 组织再生、宿主防御、血管生成、淋巴管发育和肿瘤转移。 病理性血小板血栓也是导致以下疾病的大部分发病率和死亡率的原因： 动脉血管疾病。我们对生理和心理的理解仍然存在很大差距 病理性血小板功能。以我们集体的科学成就为基础，我们解决 我们使用细胞生物学、结构生物学和计算生物学方法来弥补这些差距 已经发展起来了。我们提出的计划项目由四个项目和一个 行政核心单位。所有项目均位于佩雷尔曼医学院 宾夕法尼亚大学。三个项目基于血液肿瘤学部门 医学系；第四个位于该院的血液科 费城儿童医院儿科。项目1，更名为“小说 磷酸肌醇信号传导在 α-颗粒生物发生中的作用”，基于以下假设： 磷酸肌醇合成是 α-颗粒负载组分的重要步骤 在高尔基体中合成，巨核细胞磷酸肌醇发挥着先前的作用 在先天性巨核细胞疾病的发展中的作用尚未被认识。的目标 项目2，题为“血小板整合素结构和功能”，将使用新颖的计算和 比较 αIIbβ3 与其他整合素行为的实验技术 识别和量化导致 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 的标题是“止血和血栓形成的系统方法”。的 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 人类，从止血到血栓形成。项目 4，标题为“血小板因子 4 和肝素 在 NETosis 和脓毒症中”，将检验 NET、中性粒细胞胞外陷阱的假设 由中性粒细胞释放的染色质组成，需要部分消化并释放 DNA 和组蛋白在脓毒症期间是有毒的。因为输注了血小板因子4，以及 单克隆抗体 KKO 与血小板因子 4 和肝素复合物结合，阻断 DNA 消化，两者对败血症都有保护作用。这四个项目由一个核心单元支持 规定了该计划的共同管理需求。

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.