Lymphocyte homeostasis is controlled by the processes of hematopoietic differentiation, proliferative self-renewal, and turnover through apoptotic cell death. The importance of cell survival in regulating lymphocyte homeostasis is demonstrated by the observation that overexpression of the anti-apoptotic Bcl-2-related proteins, Bcl-2 and Bcl-xL, leads to a dose-dependent increase in lymphocyte accumulation in peripheral organs and contributes to the pathogenesis of follicular lymphoma. Germline deletion of anti-apoptotic Bcl-2-related genes leads to a failure in the development and/or survival of peripheral lymphocytes. These data suggest that the regulation of lymphocyte survival plays a critical role in the maintenance of the antigen-specific immune system. Furthermore, these data demonstrate that deregulation of apoptotic control can contribute to the pathogenesis of lymphoid malignancies. In addition to Bcl-2 proteins, recent evidence suggests that the regulation of lymphocyte survival in vivo is dependent on extracellular signal transduction. Loss of extracellular signaling can induce apoptosis through a Bcl-2-inhibitable cell death pathway initiated by mitochondrial dysfunction. The experiments in this proposal test the hypothesis that, in the absence of extracellular signaling, the basal ability of lymphocytes to take up nutrients is insufficient to maintain macromolecular synthesis or ATP production at levels needed to sustain either cell size or long-term cell survival. We seek to determine whether there are signal transduction pathways dedicated to nutrient uptake and bioenergetic control, and whether these pathways can contribute to the accumulation of excess lymphocytes and/or the pathogenesis of nonfollicular lymphomas.
Four Specific Aims are envisioned: 1) examine the ability of extracellular signaling pathways to prevent atrophy and/or promote the survival of naive lymphocytes in suspension culture; 2) identify genes that can prevent atrophy and promote lymphocyte survival; 3) examine the mechanisms by which glucose uptake is upregulated during lymphocyte proliferation; and 4) determine whether or not deregulation of genes involved in the control of nutrient uptake can contribute to the pathogenesis of lymphoma.
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