Platelet interactions with vessel wall components

描述（由申请人提供）：这项新提案的目的是确定不同成分的功能相互作用，这些成分负责细胞外基质和暴露于流动血液的细胞表面的可变血栓形成性，并定义调节血小板对这些不同刺激反应的机制。我们的具体目标是：1)表征在血管病变部位诱导血小板血栓形成的不同细胞外基质（ECM）成分。我们将使用相关血管细胞沉积的ECM，纯化的ECM成分和具有靶向基因突变或相关受体功能抑制的血小板来阐明介导血小板在血管壁相互作用的个体贡献的整合。2)表征不同ECM成分诱导血小板活化的不同途径。我们建议使用体外血流模型和具有靶向基因突变的小鼠来了解不同信号通路在血小板激活和血栓形成中在选定的ECM底物上的相互作用。3)阐明血小板与内皮细胞和血管壁其他细胞表面反应性的调控及其在血栓形成中的潜在作用机制。4)评估体外ECM、细胞和血小板组分的靶向改变对血管病变后血栓形成和稳定过程的影响。我们研究的最终目标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，以了解血小板与受伤血管相互作用的机制。本申请中概述的研究结果可能会对公众健康产生影响，因为它提供了关于正常止血和病理性动脉血栓形成的核心过程的新信息。这些发现将为抗血栓干预的几个潜在靶点提供更好的定义和特征，可能为有心脑血管事件风险的患者提供新的治疗方法。

DESCRIPTION (provided by applicant): The purpose of this new proposal is to identify the functional 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. Our specific aims are: 1) To characterize the different extracellular matrix (ECM) components that induce platelet thrombus formation at sites of vascular lesions. We 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. We propose 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 our research is to couple ex vivo studies of cells and cell products with in vivo models of vascular injury to arrive at an understanding of 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.