Normal development of multicellular organisms relies on the balance between cell proliferation, differentiation, and programmed cell death (PCD). Many types of human diseases including cancer appear to be associated with aberrant regulation of PCD and proliferation. Despite the wealth of information, mammalian-signaling pathways for survival and anti-PCD remain poorly understood. We have begun to study cell survival pathways using Akt signaling as a model system. Previous studies of Aki mostly relied on established cell lines. Hence, very little is known about the in vivo function of Akt and signaling pathways that mediate Akt anti-apoptosis activity in primary cells. Our preliminary studies using chimeric mice indicated that Akt plays an important role in hematopoietic cell survival and development. We have also identified several potential in vivo targets of Akt using peptide libraries and genetic screen approaches. The overall objective of this proposal is to understand the architecture of the Akt signaling pathway and the function of Akt in anti-apoptosis signaling and development.
The specific aims of this proposal are to: 1. Investigate the role of Akt in hematopoietic survival using primary cells and in chimera mice. 2. Elucidate the molecular mechanisms of how Akt mediates cell survival.
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