Control of lymphocyte trophic state by extrinsic signals

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Social control of cell survival and homeostasis by extrinsic signals is critical in maintaining cell survival and preventing cancer. It remains uncertain, however, why ATP production and substrate uptake fail to match intracellular demand in the absence of extrinsic signals. To determine how extrinsic signals from multiple receptor/ligand families, such as TCR/MHC, gp130/IL-6, and gamma[c]/IL-7, and growth-promoting oncogenic signaling pathways, such as Akt and c-Myc, control cellular trophic state and test the hypothesis that extrinsic signals promote survival by stimulating nutrient uptake and utilization, I propose the following aims: 1. Determine the role of extrinsic signals in T cell m e t a b o l ism, trophic state and apoptosis. A. Identify metabolic characteristics of primary T cells immediately upon isolation and after 24 hours neglect or treatment with anti-TCR, IL-6, or IL-7 as representative ligands for three distinct receptor families by measuring glycolysis, oxygen usage, glucose uptake and metabolic intermediates. B. Modulate specific metabolic pathways to determine their importance in survival and trophic state of neglected or cytokine-treated primary T cells. 2. Examine Akt and c-Myc regulation of T cell survival and trophic state. A. Measure the activation of Akt and c-Myc by TCR, IL-6R or IL-7R signaling. B. Express Akt and c-Myc and determine metabolic characteristics and trophic state in primary T cells through the generation of transgenic mice. C. Express Glut1 to determine if upregulation of Glut1 RNA is sufficient to support T cell metabolism and trophic state in the absence of extrinsic signals.