Mechanism of alphallbbeta3-mediated outside-in signaling

描述（由申请人提供）：本提案的长期目标是阐明血小板中α-11-b-β 3介导的由外向内信号转导的机制。从基础和临床研究的角度阐明这种由外向内的信号传导机制具有重要意义。具体来说，这项研究的重要性不仅源于血小板在心血管疾病中的核心作用，还源于整合素介导的由外向内信号传导机制对细胞生物学的重要性。获得对α-11-β-3介导的由外向内信号传导的分子细节的了解可以为设计能够控制至少一些有助于心血管疾病的发展和进展的血小板行为的药剂提供基本原理。该提议的长期目标将部分通过鉴定由α-11-β-3外向内信号传导所利用的衔接分子、g蛋白和激酶来实现，以在直接激活α-11-β-3的应答剂中引发颗粒分泌和血小板聚集。此外，这些信号分子之间的功能关系将被阐明。本文提出的研究的基本特征是，本研究中用于启动α-II-β-3由外向内信号传导的试剂不会直接引起α-II-β-3介导的由内向外信号传导。因此，这里的所有信号传导研究将是α-11-β-3信号传导的直接或间接结果，而不是由活化剂作用于α-11-β-3以外的受体引起的信号传导的结果。因此，α-II-β-3-起始的信号传导将不会被活化剂引起的信号传导所掩盖。从长远来看，这些实验还可以揭示引发导致分泌和活性血小板聚集的α-11-β-3由外向内信号传导所需的受体内亚基和/或受体间相互作用的类型。

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.