GENETIC CONTRIBUTION TO THE STRESS RESPONSE

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DESCRIPTION (Adapted from the applicant's abstract): The sequential collapse of different organ systems days or weeks after severe trauma, sepsis, pancreatitis, and shock, termed multiple organ dysfunction syndrome (MODS), is the most important cause of mortality and morbidity of patients admitted to the surgical intensive care unit. Recent studies have suggested that MODS is caused by an overwhelming inflammatory response as part of the host defense system. One important clinical observation is the heterogeneous response observed in patients after similar stresses. A possible explanation for this observation is that the response to stress is influenced by the patient's genetic background. Thus, the central focus of this proposal is to evaluate whether genetic diversity may contribute to the inflammatory response after stress. Inbred mouse strains will be used to test this hypothesis. This information will provide us with a better understanding of the inflammatory process and the indentification of genes that modulate the inflammatory response. This is a novel approach to a problem whose solution has been elusive using conventional methodologies. The specific aims of the project are: 1) To compare the inflammatory response between C57Bl6/J and A/J mice. The hypothesis to be tested is that the genetically distinct mouse strains, C57Bl6/J (B6) and A/J have significant differences in their inflammatory response. A comparison of the inflammatory response between these two mouse strains will be performed after two different, but related, stresses: administration of E. coli LPS, and peritonitis induced by cecal ligation and puncture (CLP). This study is also pertinent to the development of quantitative assays for the screening of recombinant inbred (RI) mouse strains (Specific Aim 2), and the identification of possible candidate genes for a positional cloning effort (Specific Aim 3). 2) To map loci responsible for strain-specific differences in the inflammatory response. The phenotypes modulating the inflammatory response of B6 (sensitive) and A/J (resistant) mice will be characterized after administration of LPS or following CLP. The assays to be used are: the infiltration of leukocytes in liver and lung, and assessment of plasma cytokine levels (TNFa and IL-B). Loci governing these responses will be mapped using RI strains (AxB and BxA). 3) Identification of candidate genes contributing to differences in the inflammatory response. The positions of those loci with the strongest contribution to the phenotypes described in Specific Aim 2 will be refined with backcross and intercross strategies (high resolution mapping) and subjected to a positional cloning effort. The results from this analysis will provide us with candidate genes that contribute to the heterogeneity of the inflammatory response.