Molecular signatures of high salt induced pathogenic T cells

描述（由申请人提供）：我们的目的是确定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道炎症。我们相信，这些信号将导致治疗靶点的识别，并有助于了解包括炎症性肠病（IBD）在内的几种人类疾病的发病机制。Th 17细胞是高度促炎细胞，对不同的自身免疫性疾病至关重要。我们开发了一个研究计划，旨在阐明炎症性Th 17细胞和抗炎调节性T细胞Tregs之间的平衡。我们的观察结果是，Th 17和Tcl 4之间的平衡对于肠道中的组织稳态是必不可少的。因此，为了鉴定Th 17细胞的新调节剂，我们在分化期间对Th 17细胞进行了时间基因表达谱分析。我们发现了一个靶点-SGK 1，这是一种在Th 17和Tcl 2中高度表达的激酶，可调节细胞的钠摄入量。我们发现SGK 1对稳定Th 17细胞表型至关重要。我们还表明，盐浓度的适度增加诱导SGK 1表达并增强Th 17细胞。 这项建议的目的是了解西方饮食中的慢性高盐摄入， 遗传易感背景，可能通过诱导致病性Th 17细胞和通过SGK 1解除保护性T细胞而触发IBD的发展。此外，这样的研究将最终有助于识别致病性Th 17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SGK 1是否调节Foxp 3 + Treg和Th 17细胞的相互分化; 2）测试高盐摄入可以通过诱导致病性Th 17和解除SGK 1介导的Treg来影响IBD的发展; 3）计算重建介导高盐效应的蛋白质和基因之间相互作用的T细胞内无偏的机制网络。这将使我们能够 确定可能与IBD易感基因重叠的潜在关键调节因子和药物靶点，并通过靶向干扰来检查它们在影响Th 17/Treg平衡和IBD发展中的作用。然后，我们可以探索IBD和其他自身免疫性疾病的潜在治疗方法。 我的短期目标是更多地了解IBD研究，并了解诱导自身免疫性T细胞介导肠道自身免疫的潜在T细胞内在和环境线索。我的长期目标是发展成为一名独立的学术研究者。我的研究计划将集中在识别可以调节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子，最终目标是为这些疾病的治疗干预确定新的靶点。

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.