Studies of Physiologic and Pathologic Platelet Plug Formation

生理和病理血小板栓子形成的研究

• 批准号: 10161819
• 负责人: LAWRENCE F BRASS
• 金额: $ 246.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10161819
• 关键词: Address; Alpha Granule; Behavior; Binding; Biogenesis; Biological; Biology; Biomedical Research; Blood Platelets; Bone Marrow; Cells; Chromatin; Coagulation Process; Complex; Cytoplasm; DNA; Development; Digestion; Disease; Fibrin; Goals; Golgi Apparatus; Hematology; Hemostatic Agents; Hemostatic function; Heparin; Histones; Host Defense; Human; Inflammation; Integrins; Knowledge; Laboratories; Mediating; Medicine; Megakaryocytes; Methods; Monoclonal Antibodies; Morbidity - disease rate; Mus; Names; Neoplasm Metastasis; Oncology; PF4 Gene; Participant; Pathologic; Pediatric Hospitals; Pennsylvania; Philadelphia; Phosphatidylinositols; Physiological; Play; Process; Research; Role; Scientific Advances and Accomplishments; Sepsis; Signal Transduction; Site; Structure; Surface; System; Techniques; Testing; Thrombosis; Thrombus; Universities; Vascular Diseases; angiogenesis; base; extracellular; lymphatic development; medical schools; mortality; neutrophil; novel; pediatric department; platelet function; programs; protein protein interaction; tissue regeneration; tumor; vascular injury

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.

程序简介摘要： 这是我们重新命名的新程序项目（HL146373-01）的重新提出 “生理和病理血小板塞形成的研究”以更准确地反映 主题项目地址。除了在地点形成止血塞 血管损伤，血小板为注射等过程做出重要贡献 组织再生，宿主防御，血管生成，淋巴发育和肿瘤转移。 病理血小板血栓也负责大部分发病率和死亡率 动脉血管疾病。我们对生理学和 病理血小板功能。在我们的集体科学成就的基础上，我们解决了 这些差距使用细胞生物学，结构生物学和计算生物学方法我们 已经开发了。我们提出的计划项目由四个项目和一个项目组成 行政核心单位。所有项目均位于Perelman医学院 宾夕法尼亚大学。三个项目位于血液肿瘤学部门 医学系；第四个基于 费城儿童医院的儿科系。项目1，重新命名为“小说 磷酸肌醇信号在α颗粒生物发生中的作用”，基于以下假设。 磷酸肌醇合成是用成分加载α颗粒的重要步骤 在高尔基体中合成，巨核细胞磷酸肌醇的作用 在先天性巨核细胞疾病的发展中无法识别的作用。目标的目标 项目2（标题为“血小板整合素结构和功能”）是使用新颖的计算和 实验技术将αIIBβ3与其他整合蛋白的行为进行比较 识别和量化负责αIIBβ3介导的纤维蛋白克隆的蛋白质蛋白质相互作用 收缩。项目3的标题为“止血和血栓形成的系统方法”。这 该项目提出的研究的目标是扩展血小板血栓的过去分析 从小鼠到大型大血管造成的形成和结构，从小鼠到大型 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和败血症中”将检验净中性粒细胞外陷阱的假设 由中性粒细胞释放的染色质组成，需要部分消化和释放DNA 和组蛋白在败血症期间有毒。因为注入血小板因子4，以及 单克隆抗体KKO与血小板因子4和肝素，块DNA结合 消化，两者都将在败血症中受到保护。这四个项目由单个核心单元支持 这提供了程序的共同行政需求。