TTUMOR NECROSIS FACTOR ACTION IN CELLS

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THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OR AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEND ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE ABSTRACT BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. DESCRIPTION: The long-term objective of the proposed research is to develop an understanding of how tumor necrosis factor (TNF) promotes its biological effects in its target cells. TNF is a cytokine with potential for the treatment of cancer that also promotes immunity, anti- viral responses, metabolic changes that accompany various diseases, the insulin-resistance of non-insulin dependent diabetes and inflammatory processes, including those that lead to arthritis. To promote the potential of TNF as a therapeutic agent and to abrogate its pathological activities requires insight into the mechanisms of TNF action. Two different TNF receptors promote cellular responses but neither contains intrinsic tyrosine kinase activity nor any motif that suggests how a signal is transmitted into the cell. Receptors without tyrosine kinase activity often bind accessory proteins that mediate interactions with signaling cascades thereby promoting biological responses. However, genes for TNF receptor-associated proteins (TRAPS) and the sequences of the proteins that they encode have not been previously identified and this may be the most significant gap in our understanding of how TNF brings about its effects. The applicant has used the yeast based two- hybrid system to discover three potentially novel genes that encode TRAPS. By analyzing which cellular responses are promoted by each TRAP, and by characterizing how TRAPS mediate signal transduction, the applicant hopes to gain fundamental insight into the molecular basis for TNF action. To accomplish this goal, the applicant will overexpress each TRAP or TRAP antisense in cells from which TNF elicits diverse responses. Control and TNF-stimulated cells will then be assayed for activation of various second messenger systems and cellular responses, such as cytotoxicity and activation of NF-kappaB.