Role of HIF-1a in T Cells During Sepsis

University Of Cincinnati, Cincinnati OH

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Abstract

Sepsis arises from a number of different clinical situations and often leads to death of patients in theintensive care unit. The clinical syndrome, sepsis, is defined as the systemic inflammatory response of the host directed specificallyat pathogens. This pathogenetically based definition represents a simple unifying concept for the development of organ dysfunction caused by infection-induced inflammatory states. As such, sepsis represents a significant challenge to the medical community. The long term goal of this project is to determine molecular mechanism by which HIF modulates T cell function during sepsis. These studies will be conducted with Ick-Cre HIF-la loxP mice after cecal ligation and puncture which will induce a lesssevere model of sepsis. These novel mice lack HIF-la only in thymically derived lymphocytes. Aim I will cddress the hypothesis that HIF-la inhibits the activationof lymphocytes and modulates production of cytokines/chemokines, thus decreasing the abilityof phagocytes to clear the poly-rmcrobial infection leading to decreased survival. Aim 2 will address the hypothesis that HIF-la modulates lymphocyte numbers by inhibiting proliferationand / or increasing lymphocyte apoptosis duringsepsis. Airr 3 will addressthe hypothesis that inhibitionof the HIF-la-mediated molecular mechanismthat directly or indirectly leads to decreased T cell IFN y production will result in increased survival during sepsis. These studies will greatly advance our knowledge of the pathophysiologyof sepsis and may identify several novel potential therapeutic targets.