Molecular signatures of high salt induced pathogenic T cells

描述(由申请人提供)：我们的目标是定义导致粘膜免疫系统激活的分子信号，从而导致自身免疫性肠炎。我们相信，这些信号将有助于确定治疗靶点，并有助于理解包括炎症性肠病(IBD)在内的几种人类疾病的发病机制。Th17细胞是高度致炎细胞，对不同的自身免疫性疾病至关重要。我们已经制定了一项研究计划，旨在阐明炎性Th17细胞和抗炎、调节性T细胞Tregs之间的平衡。我们的观察是，Th17和Tregs之间的平衡对于肠道组织的动态平衡是必不可少的。因此，为了识别Th17细胞的新调控因子，我们对Th17细胞在分化过程中的瞬时基因表达谱进行了研究。我们发现了一个靶点-SGK1，它是一种在Th17和Tregs中都高表达的激酶，调节细胞的钠摄取。我们发现SGK1是稳定Th17细胞表型的关键。我们还表明，盐浓度的适度增加可以诱导SGK1的表达，并增强Th17细胞。 这项建议的目标是了解西方饮食中的长期高盐摄入量 遗传易感背景，可能通过诱导致病的Th17细胞和通过SGK1解除保护性Tregs而触发IBD的发生。此外，这样的研究最终将有助于识别致病Th17细胞和自身免疫性疾病发展的环境触发因素。然后，我们将1)研究SGK1是否调节Foxp3+Treg和Th17细胞的相互分化；2)测试高盐摄入是否通过诱导致病Th17和解除SGK1介导的Tregs的武装来影响IBD的发展；3)通过计算重建T细胞内调节高盐效应的蛋白质和基因之间相互作用的无偏见的机械网络。这将使我们能够 识别可能与IBD易感基因重叠的潜在关键调控因子和药物靶点，并有针对性地研究它们在影响Th17/Treg平衡和IBD发展中的作用。然后，我们可以探索治疗IBD和其他自身免疫性疾病的潜在方法。 我的短期目标是了解更多关于IBD的研究，并了解诱导自身免疫T细胞介导肠道自身免疫的潜在T细胞内在和环境线索。我的长期目标是在学术环境中发展成为一名独立的调查员。我的研究计划将专注于识别能够调节T细胞亚群分化和触发T细胞介导的自身免疫性疾病的新因素，最终目标是确定这些疾病的治疗干预的新靶点。

DESCRIPTION (provided by applicant): Our objective is to define molecular signals that lead to activation of the mucosal immune system leading to autoimmune intestinal inflammation. We believe that these signals will lead to identification of therapeutic targets and help understand the pathogenesis of several human diseases including Inflammatory Bowel Disease (IBD). Th17 cells are highly proinflammatory cells that are critical for different autoimmune diseases. We have developed a research program that is aimed to elucidate the balance between inflammatory Th17 cells and the anti-inflammatory, regulatory T cells, Tregs. Our observation is that the balance between Th17 and Tregs is essential for tissue homeostasis in the gut. Thus, to identify novel regulators with Th17 cells, we performed temporal gene expression profiling of Th17 cells during differentiation. We found a target - SGK1, a kinase that is highly expressed in both Th17 and Tregs and regulates sodium intake of a cell. We discovered that SGK1 is critical stabilizing the Th17 cell phenotype. We also showed that a modest increase in salt concentration induces SGK1 expression and enhances Th17 cell. The goal of this proposal is to understand that the chronic high salt intake in western diets, on a genetically susceptible background, may act as a trigger for developing IBD by inducing pathogenic Th17 cells and disarming protective Tregs via SGK1. Furthermore, such study will ultimately facilitate the identification of environment triggers for the development of pathogenic Th17 cells and autoimmune diseases. We will then 1) investigate whether SGK1 regulates the reciprocal differentiation of Foxp3+ Treg and Th17 cell; 2) test that high salt intake can influenc the IBD development via induction of pathogenic Th17 and disarming Tregs mediated by SGK1; 3) computationally reconstruct an unbiased, mechanistic network within T cells of the interactions between proteins and genes that mediate the effect of high salt. This will allow us to identify potential key regulators and drug targets that may overlap with IBD-susceptibility genes, and to examine with targeted perturbation their roles in influencing Th17/Treg balance and development of IBD. We can then explore the potential therapeutic approaches for IBD and other autoimmune diseases. My short-term goal is to learn more about IBD research and understand the underlying T cell intrinsic and environmental cues that induce autoimmune T cells are induced to mediate gut autoimmunity. My long-term goal is to develop into an independent investigator in an academic setting. My research program will focus on the identification of new factors which can regulate T cell subsets differentiation and triggers for T cell- mediated autoimmune disorders, with the ultimate goal of identifying novel targets for therapeutic interventions for these diseases.