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

描述（申请人提供）：候选人寻求K 01职业发展奖，将包括临床研究培训，以补充他在免疫学，微生物学，遗传学和流行病学，使他能够通过调查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CD是一种炎症性肠病（IBD），由遗传易感个体中对肠细菌的粘膜免疫应答缺陷引起。 超过70个易感基因座，特别是免疫应答基因，如NOD 2/CARD 15，IRGM和ATG 16 L1，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相比，CD患者肠道微生物群的不同成员和丰度，推断微生物群在CD发病机制中可能的作用。越来越多的证据支持主要CD易感基因NOD 2/CARD 15、IRGM和ATG 16 L1在微生物抗原加工和先天免疫中的作用。 此外，研究表明，不同种族之间的微生物组特征存在显着差异。然而，目前还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，我们将调查细菌谱是否不同的载体和非载体的主要CD易感性等位基因，而专注于遗传同质的德系犹太人（AJ）人口，谁拥有最高的患病率CD相比，其他种族/种族群体。这些假设包括：1）肠道的微生物谱通过携带CARD 15、IRGM和ATG 16 L1风险变体而缓和，并且2）AJ群体中的CD风险归因于肠道中细菌物种和宿主遗传学的独特组合。 根据这些假设，候选人将招募在纽约西奈山医学院胃肠病学分部正在进行的IBD患者登记中登记的AJ CD患者，并且已经对主要CD风险进行了基因分型。 没有CD的AJ对照品将来自西奈山生物库。 我们将利用16 s rRNAdeep测序技术，然后利用生物信息学和统计学方法来表征研究受试者的肠道微生物群的疾病状态和遗传风险。通过研究遗传上更同质的人群（AJ），本研究将试图更好地了解与疾病发病机制相关的微生物组-宿主基因相互作用。 这可以帮助建立全面的诊断工具，以识别有发展CD风险的个体，并为AJ CD患者开发新的个性化治疗。此外，该项目将有助于为候选人未来的翻译研究职业生涯奠定坚实的多学科基础。

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.