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.

Public Health Relevance

Dietary factors, changes in microbiome, smoking and environmental pollutants could all play a role in the pathogenesis of IBD. In this proposal, our objective is to understand how increase in salt concentration effects mucosal inflammation with direct relevance to Crohn's disease (CD) and Ulcerative Colitis (UC). This project will help identify a novel and modifiable gut-environmental interaction that regulates IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Transition Award (R00)
Project #
5R00AI110649-03
Application #
9131613
Study Section
Special Emphasis Panel (NSS)
Program Officer
Minnicozzi, Michael
Project Start
2015-09-01
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
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