This project uses genetically modified mice to explore the roles of apoptosis in normal hematopoiesis and leukemogenesis. One major pathway to apoptosis is controlled by the oncogene bcl-2 and its relatives. Pro-apoptotic BH3-only members of this family represent regulable antagonists of their pro-survival relatives, and the phenotype of the mice lacking the BH3-only protein Bim suggests that they control particular cytotoxic responses. This hypothesis will be explored by further studies on cell survival and homeostasis in bim-/- mice, and in mice also lacking the pro-apoptotic Bax or Bid. If Bim acts through its pro-survival relatives, its loss may compensate for theirs, and that notion will be explored in mice deficient in Bcl-2 or Bcl-w as well as Bim. Because loss of Bim and gain of Bcl-2 disturb hematopoiesis very similarly, the hypothesis that Bim is a tumor suppressor will be investigated by monitoring tumor development in bim-/- mice expressing a myc transgene. The physiological roles of the BH3-only proteins Hrk and Blk will also be explored by gene disruption. Another pathway to apoptosis leads from death receptors of the TNF class through the adapter FADD to caspase 8. Its physiological and pathological roles will be explored by using a novel pan-hematopoietic expression vector (derived from the vav promoter) to drive expression of dominant interfering proteins that block the activity of FADD or caspase 8. The physiologic and pathologic consequences of blocking both the Bcl-2-regulable and death receptor pathways will be assessed by crossing lines with lesions in each, or by making mice that express the general caspase inhibitor p35 in all hematopoietic cells. Finally, vav-Cre mice will be generated, to allow application of site-specific recombination for creating conditional lesions in apoptosis throughout the hematopoietic compartment. As these studies build upon a productive ongoing program, address major issues concerning apoptosis and leukemogenesis, and exploit special resources (some unique), they should substantially help to clarify the control of apoptosis and its roles in normal homeostasis and neoplasia.
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