Dr. Brass proposes to examine intracellular signaling events that are responsible for platelet activation and megakaryocyte growth. Specifically, this proposal focuses on the role of the heterotrimeric G protein, Gz. Gz is of interest due to its restricted tissue distribution (platelets, megakaryocytes, nerve cells, but not megakaryocytic cell lines). Unlike other G proteins, Gz alpha becomes phosphorylated by PKC during platelet activation, on ser27. The goals of the present proposal are first, to identify the roles of Gz in platelets and megakaryocytes by developing a transgenic mouse model in which Gz alpha expression is knocked out in mice or repressed in megakaryocytes. Second the role of Gz in coupling cell surface receptors to intracellular effectors will be probed with a library of Gz alpha-directed antibodies and by examining the GTP:GDP exchange to detect receptor coupling to Gz. Finally, Dr. Brass proposes to define factors responsible for the selective expression of Gz alpha by studying the promoter region of this gene. It is suggested that these aims will help to define the role of Gz in platelet activation and understand factors responsible for megakaryocyte-selective gene regulation.
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