Defining novel neuro-immune pathways that regulate gut physiology

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

Project Summary/Abstract This proposal is for a five-year research career development program, focusing on the role of a key enzyme in group 3 innate lymphoid cells (ILC3s) that regulates gut physiology. Inflammatory bowel disease (IBD) is an immune-mediated inflammatory disease of the gastrointestinal tract characterized by high relapse rates, rising incidence rates, and no known cure. IBD shares common pathophysiological links with Parkinson’s disease (PD), a neurodegenerative disease with loss of dopaminergic neurons. ILC3s, the most abundant ILC in the gut, can interact with several immune and non-immune cells to promote intestinal barrier integrity, antimicrobial response, and immune tolerance. The central hypothesis is that ILC3s is equipped with a machinery to produce key factors that modulate gut inflammation and motility. The overall goal of this research is to investigate the role of these enzymes in the pathogenesis of IBD and dysmotility. To accomplish this, first, the regulation of these processes will be examined. Second, the cell-intrinsic and cell-extrinsic mechanisms by which ILC3s control gut inflammation during stress will be interrogated. Additionally, how these pathways change in human IBD will also be examined. Third, the presence of any potential links between ENS and ILC3s that control optimal gastrointestinal motility will be explored. Results of this study will delineate the role of ILC3s and associated enzymes, as well as its potential as a therapeutic target for IBD. The proposal outlines a plan to achieve my goal of becoming an expert in neuro-immune crosstalk in the context of gut inflammation and motility. Furthermore, through the proposed complementary career development plan, I will gain additional training in clinical investigation and neuroimmunology, advanced bioinformatic analysis with RNA-seq; and laboratory-based training in ILC3s biology. Throughout this research and career development activities, I will be mentored by a team lead by Dr. Gregory Sonnenberg and Dr. Timothy Wang. I am committed to a career as an independent investigator in patient-oriented translational research; and designed my training plan to acquire the knowledge and skills needed to make a meaningful and substantial contribution to the field.