Role of HIF-1a in T Cells During Sepsis

University Of Cincinnati, Cincinnati OH

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Abstract

DESCRIPTION (provided by applicant): Sepsis arises from a number of different clinical situations and often leads to death of patients in the intensive care unit. The clinical syndrome, sepsis, is defined as the systemic inflammatory response of the host directed specifically at 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-1alpha loxP mice after cecal ligation and puncture which will induce a less severe model of sepsis. These novel mice lack HIF-1alpha only in thymically derived lymphocytes. Aim 1 will address the hypothesis that HIF-1alpha inhibits the activation of lymphocytes and modulates production of cytokines/ chemokines, thus decreasing the ability of phagocytes to clear the poly-microbial infection leading to decreased survival. Aim 2 will address the hypothesis that HIF-1alpha modulates lymphocyte numbers by inhibiting proliferation and / or increasing lymphocyte apoptosis during sepsis. Aim 3 will address the hypothesis that inhibition of the HIF-1alpha-mediated molecular mechanism that directly or indirectly leads to decreased T cell IFN-gamma production will result in increased survival during sepsis. These studies will greatly advance our knowledge of the pathophysiology of sepsis and may identify several novel potential therapeutic targets.