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

描述（由申请人提供）：在该提案中，我们旨在研究低氧诱导因子-1 α（aiHIF）的活化诱导型同种型在脓毒症期间调节T细胞的抗菌应答中的作用。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细胞中起抑制作用，并且我们发现HIF-1 α阻止T细胞在脓毒症期间完全参与抗菌反应。我们的初步研究支持了这样的假设：aiHIF在脓毒症期间T细胞的负调节中发挥重要作用。使用我们最近创建的aiHIF缺陷小鼠，我们将测试aiHIF的总缺陷或T细胞特异性缺陷是否增强了小鼠脓毒症模型中的病原体破坏和存活。使用小鼠中活细菌脓毒症的体内模型，我们将测试aiHIF是否是脓毒症期间活化T细胞的主要负调节剂。此外，我们将确定aiHIF抑制T细胞的机制。预期aiHIF缺陷通过使T细胞对缺氧发炎区域中的抑制具有抗性来解除抑制T细胞，并且允许T细胞充分参与协调整体抗病原体应答，这将改善脓毒症存活。这些研究将确定aiHIF作为一种新的分子靶点，并为改善脓毒症治疗的可行策略提供原理证明，特别是当与我们最近在人类T细胞中发现的先前未知的aiHIF同种型相结合时，这将使我们的aiHIF小鼠脓毒症研究转化为人类。公共卫生相关性本提案旨在为通过预防活化诱导型HIF-1 α对T细胞的抑制来改善脓毒症治疗的新策略提供原理证明。

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.