Platelet signals and their interface with the external environment

血小板信号及其与外部环境的接口

• 批准号: 9315871
• 负责人: CHARLES S. ABRAMS
• 金额: $ 243.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315871
• 关键词: Acute myocardial infarction; Address; Affinity; Atherosclerosis; Biological Models; Blood; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Cell Surface Receptors; Coagulation Process; Collaborations; Complex; Computational Biology; Disease; Endothelial Cells; Environment; Event; Fibrin; Fibrinogen; Fluorescent Probes; Fostering; Four-dimensional; Generations; Genetic; Goals; Growth; Hemostatic Agents; Hemostatic function; Image; Individual; Inflammatory Response; Injury; Integrins; Laboratories; Ligands; Mechanics; Mediating; Molecular Conformation; Morbidity - disease rate; Mus; Pathogenesis; Pathologic; Pediatric Hospitals; Pennsylvania; Philadelphia; Phosphatidylinositols; Play; Productivity; Publications; Reaction; Recording of previous events; Regulation; Research; Research Personnel; Series; Signal Transduction; Site; Societies; Stream; Surface; Technology; Testing; Therapeutic Intervention; Thinking; Thrombin; Thrombosis; Thrombus; Time; Universities; Venous; Work; density; design; experimental study; extracellular; in vivo; in vivo Model; innovation; interest; meetings; mortality; novel; programs; regional difference; response

DESCRIPTION (Provided by applicant): This Program Project brings together six investigators at the University of Pennsylvania and Children's Hospital of Philadelphia who share related interests and provides a unified focus on the 4-dimensional regulation of hemostasis and thrombosis. The overall goal of our Program is to understand how spatially restricted events are integrated into an effective but regulated hemostatic response. This Program consists of five projects, an Imaging Core and an Administrative Core. Each project in the Program takes advantage of recent advances in technology and will utilize state-of-the-art ex vivo and in vivo model systems facilitated by the Scientific Core. This Program will provide a comprehensive description of hemostasis from its initiation at the sites of vascular injury to the formation of stable platelet plugs and thrombi, ad the resultant inflammatory response. The Investigators in the Program have a strong history of productive interaction. Together, the Projects treat hemostasis as a continuum instead of a series of discrete events simply delimited by individual scientific interests. Consequently, the proposed work will contribute to the goals of the program in a synergistic rather than additive way. Project 1 will use novel fluorescent probes designed to image the reactions of coagulation in vivo at the site of the growing thrombus under real-time. Project 2 will analyze an unusual type of platelet-mediated hemostasis at the lympho-venous junction that is stimulated by PDPN-CLEC2 interaction. Project 3 will take a mouse genetics and computation biology approach to determine the influence of the microenvironment and platelet packing density on thrombus growth. Project 4 will test the innovative hypothesis that two inter-convertible conformations of the platelet integrin ¿IIb¿3 differ in their affinity for fibrinogen and in the mechanical stabilit of the complexes they form with fibrinogen. Project 5 will define the spatially restricted signaling cascades within discrete microdomains that contribute to the synthesis of phosphorylated phosphatidylinositols (phosphoinositides) in platelets. Although the projects address different facets of platelet and coagulation function, taken together within the context of the Program, they will provide an integrated picture of regulated hemostatic function.

描述（由申请人提供）： 该计划项目汇集了宾夕法尼亚大学和费城儿童医院的六名调查员，他们具有相关的利益，并统一着重于止血和血栓形成的4维管制。我们计划的总体目标是了解如何将空间限制的事件整合到有效但受调节的止血反应中。该程序由五个项目，一个成像核心和一个管理核心组成。该计划中的每个项目都利用了技术的最新进展，并将利用科学核心准备的最先进的离体和体内模型系统。该程序将通过在血管损伤部位的启动到形成稳定的血小板塞和血栓形成止血的全面描述。该计划中的研究人员具有较强的生产互动历史。这些项目一起将止血视为连续的，而不是一系列由个人科学利益界定的离散事件。因此，拟议的工作将以协同而不是加性方式为计划的目标做出贡献。项目1将使用新型的荧光问题，以实时成像体内凝血的反应。项目2将分析淋巴接缝处的一种异常类型的血小板介导的止血，该连接受到PDPN-CLEC2相互作用的刺激。项目3将采用小鼠遗传学和计算生物学方法，以确定微环境和血小板堆积密度对血栓生长的影响。项目4将检验创新的假设，即血小板整合素的两个可逆构象在其对纤维蛋白原的亲和力以及它们与纤维蛋白原形成的复合物的机械稳定性方面有所不同。项目5将定义离散微区域内的空间限制信号级联，这有助于在血小板中合成磷酸化的磷脂酰肌醇（磷酸肌醇）。尽管项目在程序的背景下共同解决了血小板和凝结功能的不同方面，但它们将提供调节的止血功能的综合图片。