application) This application outlines the research and career plan proposed by Dr. Peter P. Sayeski concerning the role of the non-receptor tyrosine kinase, Jak2, in mediating angiotensin II growth responses. Angiotensin II is the effector molecule of the renin-angiotensin-aldosterone system which maintains hemodynamic and electrolyte homeostasis. The binding of angiotensin II to the AT1 receptor initiates tyrosine phosphorylation signaling cascades which end with increased vasoconstrictive and mitogenic growth responses. The pharmacologic inhibition of this system has been advantageous in a variety of common diseases including hypertension, heart failure and diabetic nephropathy. In response to angiotensin II, Jak2 forms a physical co-association with the AT1 receptor. Previous work by Dr. Sayeski and others suggest that Jak2 plays a critical role in mediating these tyrosine phosphorylation growth responses. The idea that the growth promoting effects of angiotensin II are dependent on Jak2 tyrosine kinase and not heterotrimeric G proteins is a novel concept. This application is designed to directly test this hypothesis. The proposed experiments in this application are based on preliminary data using newly created recombinant DNA molecules and novel cell lines. Completion of the proposed Specific Aims will provide a better understanding of (1) the biochemical nature of the AT1/Jak2 physical co-association and (2) the specific role of Jak2 in mediating angiotensin II-dependent mitogenic growth responses. The research will be performed at Emory University which contains state of the art facilities and programs that foster the development of young scientific investigators.
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