Platelet Interactions with Vessel Wall Components

项目1的目的是确定对变量负责的不同成分的相互作用 血栓形成的细胞外基质和细胞表面暴露于流动的血液，并定义 调节血小板对这些不同刺激的反应的机制。具体目标是：（1） 表征不同的细胞外基质（ECM）成分，诱导血小板血栓形成， 血管病变部位。申请人将使用相关血管细胞沉积的ECM、纯化的ECM 具有靶向基因突变或相关受体功能抑制的成分和血小板， 阐明在血管壁处介导血小板相互作用的个体贡献的整合。（二） 表征不同ECM组分诱导的血小板活化的不同途径。的 申请人提出使用离体流动模型和具有靶向基因突变的小鼠来理解 不同信号通路在血小板活化和选定ECM上血栓形成中相互作用 印刷受体. 3)阐明血小板与内皮细胞表面反应性的调节及其他 细胞的血管壁和潜在的贡献，这种机制血栓形成。4)到 评估ECM、细胞和血小板成分的靶向改变对细胞增殖过程的影响。 体内血管损伤后血栓形成和稳定。这项研究的最终目的是 将细胞和细胞产物的离体研究与血管损伤的体内模型结合起来，以了解 控制血小板与受损血管相互作用的机制。概述的研究结果， 这一应用可能会对公共卫生产生影响，因为它提供了有关过程的新信息， 是正常止血和病理性动脉血栓形成的核心。这些发现将提供一个更好的 抗血栓干预的几个潜在靶点的定义和表征， 治疗有心脑血管事件风险的患者。

The purpose of Project 1 is to identify the interplay of different constituents responsible for the variable thrombogenicity of extracellular matrices and cell surfaces exposed to flowing blood, and define the mechanisms that regulate the response of platelets to such diverse stimuli. The specific aims are: 1) To characterize the different extracellular matrix (ECM) components that induce platelet thrombus formation at sites of vascular lesions. The applicant will use the ECM deposited by relevant vascular cells, purified ECM constituents and platelets with targeted genetic mutations or functional inhibition of relevant receptors to elucidate the integration of the individual contributions that mediate platelet interactions at the vessel wall. 2) To characterize the distinct pathways of platelet activation induced by different ECM components. The applicant proposes to use ex vivo flow models and mice with targeted genetic mutations to understand the interplay of different signaling pathways in platelet activation and thrombus formation on selected ECM substrates. 3) To elucidate the regulation of platelet reactivity with the surface of endothelial cells and other cells of the vessel wall and the potential contribution of such mechanisms to thrombus formation. 4) To evaluate the effects of targeted alterations of ECM, cellular and platelet components on the process of thrombus formation and stabilization following a vascular lesion in vivo. The ultimate goal of this research is to couple ex vivo studies of cells and cell products with in vivo models of vascular injury to understand the mechanisms that govern the interaction of platelets with injured vessels. The results of the studies outlined in this application are likely to have an impact on public health by providing novel information on processes that are central to normal hemostasis and pathological arterial thrombosis. These findings will provide a better definition and characterization of several potential targets for antithrombotic intervention that may yield new treatments for patients at risk of cardiovascular and cerebrovascular events.