Mouse QTL in Endotoxic Shock

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DESCRIPTION (provided by applicant): The experiments proposed here are designed to identify genes involved in the regulation of the inflammatory response. An inflammatory response is essential to maintain homeostasis in the face of invasion from outside the organism. However, when this response is not properly regulated, it can be detrimental to the host. Multiple organ dysfunction syndrome (MODS), a clinical condition that results from an improperly regulated inflammatory response, is the most important cause of morbidity and mortality in surgical intensive care units. This condition is a complex trait, resulting from a combination of genetic, environmental and stochastic factors. There are currently no predictors as to which individual patients may be genetically predisposed. Mapping QTL contributing to this outcome is problematic in outbred, free-ranging species. A wealth of information exists about the biochemistry, cell, and organismal biology of endotoxin-induced inflammatory response. We have demonstrated that genetic variation between inbred strains of mice results in a greater or lesser inflammatory response. Robust differences in several phenotypes were observed between A/J and C57BL/6J (B6) mice. We have mapped QTL affecting two traits that vary significantly between these strains of mice, LPS-induced infiltration of PMN in the liver, and the mitogenic response of cultured splenic B cells to LPS. Several mapping strategies will be used to refine the localization of these QTL. Two loci have been chosen for initial positional cloning efforts, and specific strategies are discussed. Genes identified by this approach will be used to initiate analysis of the pathways regulating the inflammatory response at molecular, cellular and systemic levels. Where strain-specific variants are identified that account for differences in phenotype, understanding of these molecular changes will be related to statistical predictions about the mode of inheritance (loci which are dominant, recessive, additive, modifying). This information will be used to interpret and further develop methods for detecting QTL.