Early-life Risk Factors for Inflammatory Bowel Disease

This project will evaluate early-life risk factors associated with inflammatory bowel diseases (IBD), biomarker of intestinal inflammation and loss of gut microbiome diversity. Candidate: The primary objective of this application is to support Dr. Manasi Agrawal’s career development into an independent patient-oriented investigator in the field of molecular epidemiology of IBD. Dr. Agrawal’s career goal is to become a researcher and leader in the identification of modifiable early-life risk factors for IBD, risk prediction and eventually, prevention of IBD. Dr. Agrawal’s proposed training activities are in five areas: 1) advanced and life-course epidemiology, 2) advanced biostatistical methodology 3) predictive biomarker analysis, 4) principles of immunological data analysis and 5) scientific and grant writing. To achieve this, she has assembled a mentoring and advisory team led by Dr. Inga Peter, Interim Chair of the Department of Genetics and Genomic Sciences at Mount Sinai and an expert in translational -omics and data science, and Dr. Jean-Frederic Colombel, Director of the Feinstein IBD Center, Mount Sinai, a global expert in clinical and translational investigation of IBD pathogenesis, prediction and prevention. Environment: The Icahn School of Medicine at Mount Sinai 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 and is an international leader in IBD research and clinical care. Research: IBD, including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic, progressive, immune-mediated disease of the intestinal tract with significant morbidity, healthcare costs and has no cure. IBD pathogenesis involves early-life risk factors, but these are not well-understood, which impedes early intervention and prevention. Newer data suggest IBD is preceded by intestinal inflammation, loss of microbiome diversity and distinct proteomic signatures. Developing IBD risk prediction models will shed light on IBD pathogenesis, help identify at-risk individuals, and guide therapeutic and preventive strategies. In addition, determining the impact of IBD risk factors on intestinal inflammation and microbiome changes will provide further insights in IBD pathogenesis and the relevance of these changes. Therefore, our specific aims are to (1) derive and validate models to predict CD and UC risk using early-life non- genetic risk factors (2) determine if early-life IBD risk factors are associated with intestinal inflammation, and loss of gut microbiome diversity as well as correlate IBD risk signature based on its prediction model with intestinal inflammation (3) determine if inflammatory protein biomarkers in the cord serum are associated with maternal IBD status and with intestinal inflammation in the mothers and their offspring. We will study the Danish population-based cohort for Aim 1, and MECONIUM, a novel longitudinal cohort of pregnant women with and without IBD and their offspring for Aims 2 and 3. The general approaches and skills developed during this award can be applied to future studies to understand better IBD pathogenesis and toward preventive efforts.