Platelet interactions with vessel wall components

描述(由申请人提供)：这项新建议的目的是确定不同成分之间的功能相互作用，这些成分对暴露在流动血液中的细胞外基质和细胞表面的不同血栓形成能力负责，并确定调节血小板对这种不同刺激的反应的机制。我们的具体目标是：1)鉴定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。我们将利用相关血管细胞、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沉积的ECM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)明确不同ECM成分诱导血小板活化的不同途径。我们建议使用体外流动模型和具有靶向基因突变的小鼠来了解不同信号通路在选定的ECM底物上对血小板激活和血栓形成的相互作用。3)阐明血小板与血管壁内皮细胞和其他细胞表面反应性的调节及其在血栓形成中的潜在作用。4)评价靶向改变ECM、细胞和血小板成分对血管损伤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品的体外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。本申请中概述的研究结果可能会对公众健康产生影响，因为它提供了有关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，这些靶点可能为有心脑血管事件风险的患者产生新的治疗方法。

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.