Platelet interactions with vessel wall components

血小板与血管壁成分的相互作用

• 批准号: 6852337
• 负责人: Zaverio M Ruggeri
• 金额: $ 45.85万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-17 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6852337
• 关键词: cell cell interaction; cell component structure /function; cell population study; clinical research; extracellular matrix; hemodynamics; human tissue; laboratory mouse; platelet activation; platelets; thrombosis; vascular endothelium

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.

描述（由申请人提供）：该新建议的目的是确定负责导致细胞外基质和细胞表面可变血栓形成的不同成分的功能相互作用，并定义了调节血小板对这种多样性刺激的反应的机制。我们的具体目的是：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，具有靶向遗传突变的纯化ECM成分和血小板沉积的ECM，或对相关受体的功能抑制，以阐明介导血管壁上血小板相互作用的单个贡献的整合。 2）表征不同的ECM成分引起的血小板激活的不同途径。我们建议使用具有靶向遗传突变的离体流量模型和小鼠，以了解在选定的ECM底物上血小板激活和血栓形成中不同信号通路的相互作用。 3）阐明血小板反应性与血管壁的内皮细胞和其他细胞的表面以及这种机制对血栓形成的潜在贡献。 4）评估ECM，细胞和血小板成分的靶向改变对体内血栓形成和稳定过程的影响。我们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相结合，以了解控制血小板与受伤血管相互作用的机制。该应用中概述的研究结果可能会通过提供有关正常止血和病理动脉血栓形成的过程的新信息，从而对公共卫生产生影响。这些发现将为抗血栓干预的几个潜在靶标提供更好的定义和表征，这可能会为患有心血管和脑血管事件风险的患者提供新的治疗方法。