Lymphocytes lack the ability to take up sufficient nutrients from the extracellular environment to maintain survival in the absence of extrinsic signals. Even quiescent lymphocytes are dependent on extracellular signals to direct the nutrient uptake necessary for viability. The inability to take up extracellular nutrients on a cell-autonomous basis also limits the ability of lymphocytes to engage in antigen receptor-induced proliferation unless the cells simultaneously receive extracellular signals that direct nutrient uptake and metabolism to sufficient levels to meet the increased bioenergetic demands of growth and proliferation. Over the last several years, we have demonstrated that one way in which costimulatory receptors, such as CD28, and cytokines, such as IL-2, contribute to cell growth is through directly stimulating antigen-activated lymphocytes to increase their uptake and metabolism of glucose and amino acids. Two independent metabolic signaling pathways have been identified in lymphocytes: the PISK/Akt and JAK/STAT/Pim pathways. These two signaling pathways have direct and partially overlapping effects on the ability of lymphocytes to take up essential nutrients and utilize these nutrients to fuel ATP production and protein, lipid, and nucleotide synthesis. Although both pathways are used during the growth and proliferation of non- transformed lymphocytes, constitutive activation of either Akt-1 or Pim-2 is sufficient to activate nutrient uptake to levels that support both cell autonomous survival and antigen receptor-induced cell growth and proliferation. In this continuation proposal, we seek to investigate the molecular basis by which T cells utilize the PISK/Akt and JAK/STAT/Pim pathways to convert exogenous glucose into the lipids and nucleotides needed for cell growth and/or proliferation.
Three specific aims are envisioned: 1) Determine the role of glucose-dependent lipid production in lymphocyte growth and survival;2) Study the role of glucose- dependent synthesis of nucleotide precursors and NADPH in the regulation of lymphocyte proliferation;and 3) Define whether inhibitors of the glucose-dependent metabolic pathways activated by the PISK/Akt or JAK/STAT/Pim pathways can selectively impair the growth of spontaneous lymphomas. A more thorough characterization of how costimulatory receptors and cytokines regulate the metabolic processes of lipid and nucleotide biosynthesis may lead to the development of novel therapies for the prevention or treatment of lymphoma.
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