Mechanism of alphallbbeta3-mediated outside-in signaling

描述(申请人提供)：这项建议的长期目标是阐明α-11-b-β3介导的外向内信号转导在血小板中的机制。从基础研究和临床研究的角度阐明这一外向内信号在人血小板中的作用机制具有重要意义。具体地说，这项研究的意义不仅来自于血小板在心血管疾病中的核心作用，也源于整合素介导的自外向内信号机制对细胞生物学的核心重要性。深入了解α-11-β-3介导的外向内信号的分子细节，可能为设计一种能够控制至少部分导致心血管疾病发生和发展的血小板行为的药物提供理论基础。这项建议的长期目标将会实现，部分是通过鉴定适配器分子、g-蛋白和激酶，这些适配分子、g-蛋白和激酶被外向内信号用来在直接激活α-11-β-3的反应剂中诱导颗粒分泌和血小板聚集。此外，还将阐明这些信号分子之间的功能关系。这项研究的基本特征是，本研究中用于启动α-II-β-3自外向内信号传递的药物不会直接导致α-11-β-3介导的内向外信号传递。因此，这里的所有信号研究都将是α-11-β-3信号传递的直接或间接结果，而不是激活剂作用于α-11-β-3以外的受体而引起的信号传递的结果。因此，α-11-β-3启动的信号不会被激活剂引起的信号所掩盖。从长远来看，这些实验还可能揭示受体内亚单位和/或受体间相互作用的类型，这是启动α-11-β-3外-内信号所必需的，从而导致分泌和活跃的血小板聚集。

DESCRIPTION (provided by applicant): The long term objective of this proposal is to elucidate the mechanism of alpha-ll-b-beta 3-mediated outside-in signal transduction in platelets. Elucidation of the mechanism of this outside-in signaling in human platelets is significant from the perspectives of both basic and clinical research. Specifically, the significance of the proposed research stems not only from the central role of platelets in cardiovascular disease but also from the central importance of the mechanism of integrin-mediated outside-in signaling to cell biology. Gaining insight into the molecular details of alpha-ll-beta-3-mediated outside-in signaling may provide a rationale for the design of a pharmaceutical agent able to control at least some of the platelet behavior that contributes to the development and progression of cardiovascular disease. The long term objective of this proposal will be attained, in-part by identifying the adapter molecules, g-proteins and kinases that are utilized by alpha-ll-beta-3 outside-in signaling to elicit granule secretion and platelet aggregation in response agents that directly activate alpha-ll-beta-3. Additionally, the functional relationship between these signaling molecules will be elucidated. The essential feature of the research proposed here is that the agents used in this study to initiate alpha-II-beta-3 outside-in signaling will not directly cause alpha-ll-beta-3-mediated inside-out signaling. Therefore, all of the signaling studies here will be the direct or indirect result of alpha-ll-beta-3 signaling, not the result of signaling caused by the activating agent acting on a receptor other than alpha-ll-beta-3. Thus, the alpha-ll-beta-3-initiated signaling will not be obscured by signaling caused by activating agent. In the long run, these experiments may also reveal the type of intra-receptor subunit and/or inter-receptor interactions that are required to initiate alpha-ll-beta-3 outside-in signaling that results in secretion and active platelet aggregation.