Activation-inducible HIF-1alpha in Regulation of T Cells During Bacterial Sepsis

描述(由申请人提供)：在这项建议中，我们旨在研究低氧诱导因子-1α的激活诱导亚型(AiHIF)在脓毒症期间调节T细胞抗细菌反应中的作用。我们的假设表明，aiHIF是改善脓毒症患者抗菌清除的潜在靶点。这一假设是基于我们的发现，即aiHIF在TCR激活的T细胞中发挥抑制作用，我们发现HIF-1α阻止T细胞在脓毒症过程中充分发挥抗菌作用。我们的初步研究支持这一假设，即在脓毒症过程中，aiHIF在T细胞的负调节中起主要作用。使用我们最近创建的aiHIF缺陷小鼠，我们将测试aiHIF的全部缺陷或T细胞特异性缺陷是否增强了小鼠脓毒症模型中病原体的破坏和存活率。利用活体小鼠细菌败血症模型，我们将测试aiHIF是否是脓毒症期间激活的T细胞的主要负调节因子。此外，我们还将确定aiHIF抑制T细胞的机制。AiHIF缺陷有望通过使T细胞在缺氧性炎症区域抵抗抑制来解除抑制，并允许T细胞充分参与整体抗病原体反应，这将提高脓毒症的存活率。这些研究将确定aiHIF是一个新的分子靶点，并为改进脓毒症治疗的可行策略提供原理证据，特别是当结合我们最近在人类T细胞中发现的以前未知的aiHIF亚型时，这将使我们对aiHIF的小鼠败血症研究转移到人类身上。公共卫生相关性这项建议旨在为通过预防活化诱导的HIF-1α抑制T细胞来改善脓毒症治疗的新策略提供原则证据。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.