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，他们分享相关利益，并统一关注止血和血栓形成的四维调节。我们计划的总体目标是了解空间限制事件如何整合到有效但受调控的止血反应中。该计划包括五个项目，一个成像核心和一个行政核心。该计划中的每个项目都利用了最新的技术进步，并将利用科学核心促进的最先进的离体和体内模型系统。该计划将提供从血管损伤部位开始止血到稳定血小板栓和血栓形成以及由此产生的炎症反应的全面描述。该计划中的调查人员有着丰富的互动历史。总之，这些项目将止血视为一个连续体，而不是一系列仅由个人科学兴趣界定的离散事件。因此，拟议的工作将有助于以协同而不是添加剂的方式实现该计划的目标。项目1将使用新型荧光探针，用于实时成像血栓生长部位的体内凝血反应。项目2将分析一种不寻常的血小板介导的止血在淋巴静脉交界处，这是由PDPN-CLEC 2相互作用刺激。项目3将采用小鼠遗传学和计算生物学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将检验血小板整合素<$IIb <$3的两种可相互转化的构象在它们对纤维蛋白原的亲和力和它们与纤维蛋白原形成的复合物的机械稳定性方面不同的创新假设。项目5将定义离散微域内的空间限制性信号级联，这些信号级联有助于血小板中磷酸化磷脂酰肌醇（磷酸肌醇）的合成。尽管这些项目涉及血小板和凝血功能的不同方面，但在该计划的背景下，它们将提供受管制止血功能的综合情况。

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.