The role of Akt in platelet signaling and thrombosis

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DESCRIPTION (provided by applicant): My long-term career objectives are to obtain a faculty position at a major research institution, where the resources exist to support a research specialty in the vascular complications of diabetes. My short-term goals are to use the project supported by this research career grant award both to develop increasing independence as an investigator and to broaden my developing expertise in signal transduction and platelet biology to include a more complete understanding of the role of the platelet in vivo. The laboratory of Dr. Brass here in the Hem-Onc Division of the Department of Medicine at Penn provides an ideal environment in which to manage both the scientific and career transition. Scientifically, weekly data clubs and seminar series run by local experts in platelet biology, diabetes, hematology, and pharmacology provide lively forums for discussion of the current developments in each specialty, many of which lead to fruitful collaborations. With regard to my career development, both my sponsor and the Chair of Medicine are committed to supporting my transition to a full faculty position within 3 years. The scientific objective of this proposal is to understand the intracellular signaling events that regulate platelet activation to gain a better understanding of their contribution to thrombosis. In the following 3 Specific Aims, this proposal will test the hypothesis that Akt1 and Akt2 play a critical role in the signaling pathways that lead to platelet aggregation and stabilization of the platelet plug formed in vivo. Aim 1) Does Akt contribute to platelet activation and platelet aggregation in vitro? These studies will continue work that I have already begun to determine whether mice lacking multiple alleles of Akt1 and Akt2 have defects in fibrinogen binding, granule secretion, or clot retraction. Aim 2) How is Akt involved in signaling pathways leading to platelet activation? The effects of low expression of platelet Akt on activation of the GTPase Rap1 and phosphorylation of the beta 3 tail of integrin alpha lIb beta 3 will be tested since these events have been associated with platelet aggregation. Aim 3) Does Akt contribute to platelet plug formation in vivo? We will measure bleeding time, blood flow after ferric chloride injury of the carotid artery, and thromboembolism in Akt-deficient versus wildtype mice to determine the effect of Akt on hemostasis and thrombosis.