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

描述(申请人提供)：应聘者寻求K01职业发展奖，其中将包括临床研究培训，以补充他在免疫学、微生物学、遗传学和流行病学的多学科培训，并使他能够通过研究肠道微生物群在重大遗传风险影响下克罗恩病(CD)中的作用来推进他的科学生涯。CD是一种炎症性肠病(IBD)，由遗传易感个体对肠道细菌的粘膜免疫反应缺陷引起。超过70个易感基因，特别是免疫反应基因，如NOD2/CARD15，IRGM和ATG16L1，与欧洲血统的人患CD的风险有关。以往的研究已经证实，与健康对照组相比，CD患者肠道微生物区系具有明显的成员和丰富性，推测微生物群在CD发病机制中可能发挥作用。越来越多的证据支持主要的CD易感基因NOD2/CARD15、IRGM和ATG16L1在微生物抗原的加工和天然免疫中的作用。此外，研究表明，不同种族之间的微生物群谱存在显著差异。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富有关。在这项研究中，我们将调查主要CD易感等位基因携带者和非携带者之间的细菌图谱是否存在差异，同时关注遗传同质的德系犹太人(AJ)人群，与其他民族/种族群体相比，AJ人群CD的患病率最高。这些假设包括：1)肠道的微生物谱受到CARD15、IRGM和ATG16L1风险变异的影响，2)AJ人群中的CD风险可归因于肠道和宿主基因中细菌种类的独特组合。 在这些假设下，候选人将招募AJ CD患者，登记在纽约西奈山医学院消化内科正在进行的IBD患者登记中，并且已经对主要CD风险进行了基因分型。没有CD的AJ控制将来自西奈山生物库。我们将利用16S rRNA深度测序技术以及生物信息学和统计学方法来表征研究对象的肠道微生物区系，以了解疾病状况和遗传风险。通过对遗传同质性更高的群体(AJ)的研究，本研究将试图更好地理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，以识别患有CD的风险个体，S，以及为AJ CD患者开发新的个性化治疗。此外，这个项目将有助于为候选人未来在翻译研究方面的职业生涯建立一个强大的多学科基础。

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.