Ischemia/reperfusion and sepsis are associated with increased intestinal epithelial and lymphocytic apoptosis. The principal investigator for this career development award is a critical care surgeon, whose long-term career objective is to develop mechanistic insights into the body's response to shock and sepsis, leading to improved survival in the surgical intensive care unit. As immediate goals, the applicant seeks to elucidate the role of intestinal apoptosis in shock and sepsis and to develop an expertise in immunology to assess crosstalk between the intestinal epithelium and the immune system. This research proposal will provide the framework for achieving these goals through a period of formal instruction and investigation supervised by mentors with established track records of developing independent investigators. Septic patients have markedly increased levels of intestinal and lymphocytic apoptosis. In addition, animal models of shock and sepsis show elevated levels of intestinal and immune apoptosis, with a survival advantage conferred on transgenic mice which overepress the antiapoptotic mediator, Bcl-2, in lymphocytes. The applicant hypothesizes that alterations in apoptosis in the intestinal epithelium contribute to the morbidity and mortality resulting from ischemia/ reperfusion and/or sepsis. To address this hypothesis, the applicant's two interlocking specific aims are (1) to determine the relationship between ischemia/ reperfusion and/or sepsis and apoptosis in the intestinal epithelium and assess the therapeutic potential of decreasing programmed cell death via alterations in Bcl-2, and (2) to demonstrate crosstalk between the intestine and the immune system in ischemia/reperfusion and/or sepsis-induced apoptosis. Transgenic animals overexpressing or deficient in Bcl-2 and lymphocyte deficient Rag-1-/- animals will be utilized to determine the mechanisms by which alterations in death levels in one organ system affect the other.
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