Intestinal Stem Cell Metabolism in Inflammatory Bowel Disease Mucosal Healing

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Project Summary/Abstract Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a complex disease that results in long-term inflammation within the intestine. Approximately 3.1 million individuals in the United States are currently living with IBD with 70,000 newly identified cases each year. This presents a significant financial burden on individuals and the economy, costing over $14.6 billion annually in the United States. Patients with IBD experience cycles of inflammation and tissue damage followed by periods of repair and remission. The majority of immunotherapies for IBD treatment have been focused on modifying the immune response, which are highly effective, but nearly a third of patients relapse within 12 months. Redirecting our focus on how the mucosa is repaired will likely provide an added benefit in IBD treatment when coupled with immune modulating therapies. The unique ability of intestinal stem cells (ISCs) to self-renew and differentiate into functional epithelial cells makes them an indispensable component of tissue repair. In the gut, different populations of damage-associated ISCs exist, including a ISC population that emerges during colitis-associated inflammation. To better understand this population, we developed a 3-D murine organoid model system that enriches for these cells. This system will be utilized to study how cell metabolism impacts the reparative function of colitis-associated ISCs. The use of metabolite analysis via mass spectrometry and metabolic bioenergetic analysis using a Seahorse XFe96 Analyzer will allow us to generate a metabolic profile for these cells. We are also developing a novel mouse reporter line to study how glucose transporters impact the reparative function of colitis-associated ISCs in an intestinal injury-repair model of inflammation. Successful completion of this grant will allow us to better understand how the cell metabolism of colitis-associated ISCs impacts mucosal healing. Our long-term goal is to identify biomarkers of colitis- associated ISCs to define mucosal healing and disease remission more accurately. A better understanding of the molecular processes that influence colitis-associated ISC function will encourage the development of novel therapeutics that help to regenerate the damaged epithelium. This work is being conducted at the Rangos Research Center of UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, which is an outstanding research environment that provides the trainee with the physical resources, research cohorts, and intellectual resources to successful complete this work. The detailed training plan designed will help develop the trainee’s scientific expertise in ISC metabolism, biomarker discovery, and IBD, and facilitate the transition into an independent investigator in IBD research.