Interplay of Gut Microbiome and Host Genes in Crohn's Disease

描述（由申请人提供）：候选人寻求K01职业发展奖，该奖项将包括临床研究培训，以补充其在免疫学，微生物学，遗传学和流行病学的多学科培训，并使他能够通过研究肠道微生物组在克罗恩病（CD）中的作用来推进他的科学事业在主要遗传风险的影响下。乳糜泻是一种炎症性肠病（IBD），在遗传易感个体中由肠道细菌引起的粘膜免疫反应缺陷引起。超过70个易感位点，特别是免疫反应基因，如NOD2/CARD15、IRGM和ATG16L1，与欧洲血统个体的CD风险相关。先前的研究已经确定了与健康对照组相比，乳糜泻患者肠道微生物群的独特成员和丰度，推断了微生物群在乳糜泻发病机制中的可能作用。越来越多的证据支持主要的CD易感基因NOD2/CARD15、IRGM和ATG16L1在微生物抗原和先天免疫过程中的作用。此外，研究表明，不同种族之间的微生物组谱存在显著差异。然而，目前尚不清楚主要遗传风险等位基因的携带是否与肠道中任何特定微生物物种的丰度相关。在这项研究中，我们将调查主要乳糜泻易感性等位基因携带者和非携带者之间的细菌谱是否存在差异，同时关注遗传同质的德系犹太人（AJ）人群，他们与其他种族/种族群体相比具有最高的乳糜泻患病率。这些假设包括：1)肠道微生物谱受到携带CARD15、IRGM和ATG16L1风险变异体的调节；2)AJ人群的CD风险可归因于肠道细菌种类和宿主遗传的独特组合。测试

DESCRIPTION (provided by applicant): 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.