The candidate seeks a K01 career development award that will encompass training in clinical research to complement his multidisciplinar training in immunology, microbiology, genetics and epidemiology and enable him to advance his scientific career by investigating the role of the gut microbiome in Crohn's diseae (CD)under the influence of major genetic risks.CD is an inflammatory bowel disease (IBD) resulting from defects in the mucosal immune response to enteric bacteria in genetically susceptible individuals. Over 70 susceptibility loci, particularly immune response genes such as NOD2/CARD15, IRGM and ATG16L1, have been associated with CD risk in individuals of European ancestry. Previous studies have established the distinct membership and abundance of the gut microbiota in CD patients compared with healthy controls, inferring a possible role of the microbiome in CD pathogenesis. Accumulating evidence supports the role of the major CD susceptibility genes, NOD2/CARD15, IRGM and ATG16L1 in the processing of microbial antigens and innate immunity. Moreover, studies showed significant differences in microbiome profiles among ethnic groups. However, it is unclear whether carriage of the major genetic risk alleles correlates with an abundance of any particular microbial species in the gut. In this study we will investigate whether bacterial profile differs between carriers and non-carriers of the major CD susceptibility alleles while focusing on a genetically homogeneous Ashkenazi Jewish (AJ) population, who has the highest prevalence of CD comparing with other ethnic/racial groups. The hypothesizes include: 1) the microbial profile of the gut is moderated by the carriage of CARD15, IRGM and ATG16L1 risk variants and 2) the CD risk in the AJ population is attributable to the unique combination of bacterial species in the gut and host genetics.To test these hypotheses, the candidate will recruit AJ CD patients enrolled in an ongoing registy of patients with IBD in the Division of Gastroenterology at The Mount Sinai School of Medicine, New York and already genotyped for the major CD risks. AJ controls without CD will come from the Mount Sinai Biobank. We will utilize 16s rRNAdeep sequencing technique followed by bioinformatics and statistical approaches to characterize the gut microbiota in study subjects with regard to disease status and genetic risks. By studying a more genetically homogeneous population (AJ), this study will attempt to gain a better understanding of the microbiome-host gene interaction associated with disease pathogenesis. This can help build comprehensive diagnostic tools to identify individuals at risk of developing CD, s well as develop novel personalized treatments for AJ CD patients. In addition, this project will help to establish a strong multidisciplinary foundation for the candidate's future career in translational research.
The membership and abundance of the gut microbiome in CD patients are different from healthy controls.Major CD risk-associated genes, CARD15, IRGM and ATG16L1, detected by large genome-wide associationstudies, have been shown to play an essential role in the processing of microbial antigens and host innateimmunity. The goal of this project is to investigate the interplay between the host genetic make-up and the gutmicrobiota in CD pathogenesis
