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导致自身免疫性肠道炎症的分子信号。我们相信这些信号将有助于确定治疗靶点，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。Th17细胞是高度促炎细胞，对不同的自身免疫性疾病至关重要。我们已经开发了一个研究项目，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之间的平衡对肠道组织稳态至关重要。因此，为了鉴定Th17细胞的新调控因子，我们对Th17细胞在分化过程中进行了时间基因表达谱分析。我们发现了一个靶标- SGK1，一个在Th17和Tregs中高度表达并调节细胞钠摄入量的激酶。我们发现SGK1是稳定Th17细胞表型的关键。我们还发现适度增加盐浓度可诱导SGK1表达并增强Th17细胞。

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.