Mechanism of alphallbbeta3-mediated outside-in signaling

University Of Memphis, Memphis TN

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Abstract

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.