Tumor necrosis factoralpha (TNFalpha) is a pleiotropic cytokine involved in growth and development, and in the host response to inflammation. Inappropriate production of TNFalpha and activation of TNFalpha dependent inflammatory and apoptosis- inducing pathways have been implicated in the pathogenesis of several chronic and acute inflammatory processes. Current approaches to identify the contribution of individual gene products to TNFalpha mediated injury have relied on the development of transgenic and knockout mice. Although powerful, these techniques are inherently limited because they can only identify the contribution of known genes in previously described pathways. The present R21 application proposes an alternative scientific approach to identify novel genetic intervals and genes specifically involved in sensitivity and resistance to TNFalpha/p55 TNF receptor I mediated hepatocyte apoptosis. Specifically, we propose to conduct a quantitative trait loci analysis to identify regions in the mouse (C57BL/6 and NOD) genome that may contribute to the TNFalpha mediated apoptosis. We have made the novel observation that the NOD mouse sensitized with D-galactosamine is highly resistant to both lipopolysaccharide (LPS) and TNFalpha induced hepatocyte apoptotic injury. Although these mice have no observable defect in their ability to bind human TNFalpha, the NOD mouse has a markedly reduced increase in hepatocyte caspase-3 activity, reduced hepatocyte injury and apoptosis, and increased survival to human TNFalpha. Using the sensitive C57BL/6 and resistant NOD mouse, the three specific aims of this application are: 1. To identify by quantitative trait loci analysis, regions in the mouse genome that contribute to TNFalpha/p55 TNF receptor I mediated signaling of hepatocyte apoptotic injury, 2. To dissect phenotypic abnormalities in the function of the p55 TNF receptor signaling complex from primary hepatocytes obtained from C57BL/6 and NOD parentals, and from NODx(NODxB6) offspring, and 3. Using 'marker assisted selection protocols', to initiate the generation of congenic mouse strains be breeding susceptibility intervals of the C57BL/6 mouse into the resistant NOD mouse.
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