Platelet signals and their interface with the external environment

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研究人员，他们分享了相关的兴趣，并统一关注止血和血栓形成的4维调节。我们计划的总体目标是了解空间受限的事件是如何整合到有效而规范的止血反应中的。该计划由五个项目组成，一个是成像核心，一个是管理核心。该计划中的每个项目都利用了最新的技术进步，并将利用由科学核心促进的最先进的体外和体内模型系统。本计划将全面描述从血管损伤部位开始的止血，到稳定的血小板堵塞和血栓的形成，以及由此产生的炎症反应。该项目的研究人员有很强的富有成效的互动历史。总而言之，这些项目将止血视为一个连续体，而不是简单地由个人科学兴趣界定的一系列离散事件。因此，拟议的工作将以协同而不是相加的方式促进方案的目标。项目1将使用新的荧光探针，旨在实时成像体内血栓生长部位的凝血反应。项目2将分析PDPN-CLEC2相互作用刺激的一种不寻常类型的血小板介导的淋巴-静脉连接处止血。项目3将采用小鼠遗传学和计算生物学的方法来确定微环境和血小板堆积密度对血栓生长的影响。项目4将测试这一创新假设，即两种可相互转换的血小板整合素IIb构象3在与纤维蛋白原的亲和力以及它们与纤维蛋白原形成的络合物的机械稳定性方面存在差异。项目5将确定离散微域内的空间受限信号级联，这些信号级联有助于在血小板中合成磷酸化磷脂酰肌醇(磷脂酰肌醇)。尽管这些项目涉及血小板和凝血功能的不同方面，在该计划的背景下放在一起，但它们将提供调节止血功能的综合图景。

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.