In this proposal we aim to investigate a role of the Activation-inducible isoform of Hypoxia-inducible Factor- 1alpha (aiHIF) in regulation of anti-bacterial response of T cells during sepsis. Our hypothesis indicate aiHIF as a potential target for improvement of anti-bacterial clearance in septic patients. This assumption is based on our findings that aiHIF plays inhibitory role in TCR-activated T cells, and we found that HIF-1alpha prevents T cells from fully contribute into anti-bacterial response during sepsis. Our preliminary studies support the hypothesis that aiHIF plays major role in the negative regulation of T cells during sepsis. Using our recently created aiHIF-deficient mice we will test whether the total or T-cell-specific deficiency of aiHIF enhances the pathogen destruction and survival in murine sepsis models. Using in vivo models of live bacterial sepsis in mice we will test whether aiHIF is a major negative regulator of activated T cells during sepsis. In addition, we will determine the mechanism of T-cell inhibition by aiHIF. The aiHIF-deficiency is expected to de-inhibit T cells by rendering them resistant to inhibition in hypoxic inflamed areas, and to allow T cells to fully participate in orchestrating the overall anti-pathogen response, which will improve sepsis survival. These studies will identify aiHIF as a novel molecular target and provide proof of a principle for a feasible strategy to improve therapy of sepsis, especially when combined with our recent discovery of previously unknown aiHIF isoform in human T cells that will allow our mouse sepsis studies of aiHIF to translate into humans.
This proposal aims to provide proof of principle for a novel strategy of improving the therapy of sepsis by prevention of T cells inhibition by activation-inducible HIF-1alpha.
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