THE ROLE OF PL3K IN THROMBOPOIETIN SIGNALING

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(Adapted from applicant's abstract) This K08 proposal outlines a research plan designed to give the applicant, Dr. Amy E. Geddis, the scientific training and career development necessary for a successful career in academic medicine and basic science. The proposed research will characterize the role of phosphatidylinositol 3-kinase (P13K) in cell survival and proliferation in response to thrombopoietin (TPO). TPO is the primary regulator of megakaryo- cyte (MK) development and plays an important role in hematopoiesis in general, but the mechanisms by which its receptor, Mpl, signals to stimulate cell survival and proliferation are incompletely understood. Our preliminary data suggest a role for P13K in these processes. The proposal outlines a strategy combining the use of kinase inhibitors and inducible expressed dominant negative kinases to identify elements of the P13K pathway that are important for its function in mediating survival and proliferation in response to TPO. In addition, several candidate pathways in apoptosis and proliferation will be evaluated for P13K-dependent regulation by TPO. Finally, the platelet lowering drug Anagrelide, will be evaluated for its potential interference with P13K signaling by TPO. Proposed studies will involve both Mpl-expressing cell lines as well as primary murine MK progenitors. The results of these studies will lead to a better understanding of the mechanisms by which TPO signals to promote cell survival and proliferation. Characterization of TPO signaling is critical in order to understand normal MK development, and to understand the implications of therapeutic modulation of thrombopoiesis for example involving the clinical use of TPO or Anagrelide. The University of Washington provides a strong research environment for this proposal with many faculty members engaged in related studies (hematopoiesis, signal transduction, biochemistry, apoptosis, molecular biology) whose advise and guidance will be available. There are ongoing seminars and courses in relevant areas, and the proximity of the Fred Hutchinson Cancer Research Center provides an additional resource. Dr. Kaushansky and the advisory panel, formed specifically for the aims of this proposal, will oversee the applicant's research and academic progress. A defined plan of training is presented in which the applicant will develop the experience and skills necessary for success as an independent investigator in Hematology.