Characterizing the Biologic Evolution of Crohn's Disease Like Pouch Inflammation in Ulcerative Colitis Patients After Restorative Proctocolectomy with Ileal Pouch Anal Anastomosis

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This project will characterize the genetic variants, ileal transcriptome, microbial and metabolomic profiles in patients with medically refractory ulcerative colitis (UC) who require restorative proctocolectomy (RPC) with ileal pouch anal anastomosis (IPAA) and subsequently develop Crohn’s Disease-like pouch inflammation (CDLPI). The goal is to identify the at risk -omic features associated with CDLPI. Candidate: The primary objective of this application is to support Dr. Maia Kayal’s development into an independent, patient-oriented translational investigator in the field of inflammatory bowel disease (IBD). Dr. Kayal’s career goal is to become an independent researcher with expertise in the integration of analytic methodologies to answer high-impact clinical questions in the field of IBD. To achieve this goal, Dr. Kayal has devised a training plan that is focused on the development of skills in: 1) longitudinal cohort analysis, 2) biological interpretation of transcriptome analysis, 3) clinical application of microbiome and metabolome analysis, and 4) clinical incorporation of statistical genetics. She has assembled a powerful multidisciplinary mentorship team at the Icahn School of Medicine at Mount Sinai (ISMMS) with (1) Dr. Marla Dubinsky, Professor of Medicine and Pediatrics, Chief of Pediatric Gastroenterology, and Co-Director of the Feinstein IBD Center, (2) Dr. Judy Cho, Professor and Dean of Translational Genetics, Director of the Institute for Personalized Medicine, and (3) Dr. Jeremiah Faith, Associate Professor in the Department of Genetics and Genomic Sciences and Faculty Director of the Microbiome Translational Center. Environment: The ISMMS has a strong tradition of outstanding research and is one of the top 20 medical schools in NIH funding. The Mount Sinai Division of Gastroenterology is consistently considered one of the top 10 divisions in the country by US News and World Report for research and clinical care. Research: Up to 30% of patients with treatment refractory UC will require surgery, the most common of which is the RPC with IPAA. This continence preserving procedure involves the removal of the colon and rectum, construction of a pouch from ileum to serve as an internal pelvic reservoir for stool, and restoration of intestinal continuity. Approximately 20% of patients develop CDLPI within two years of their final surgical stage, and up to 50% of these patients do not respond to standard IBD therapies and require surgical pouch removal and the creation of a permanent ostomy. To date, there is no way to predict before colon removal which patient with UC will develop CDLPI and pouch failure. We propose to characterize the genetic variants, ileal transcriptome, microbial and metabolomic profiles associated with CDLPI in patients with UC who undergo RPC with IPAA. We hypothesize that patients who develop CDLPI harbor distinctive at risk genetic and ileal transcriptomic features present at the time of colectomy before pouch creation, and that CDLPI is triggered over time by exposure to specific microbiota.