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

项目摘要 应聘者申请R03补助金，这将扩大他在临床领域K01支持的职业发展 研究以补充他在免疫学、微生物学、遗传学和流行病学方面的多学科培训 并使他能够通过研究肠道真菌生物群在克罗恩病中的作用来推进他的科学生涯 疾病(CD)在重大遗传风险的影响下。 CD是一种炎症性肠病(IBD)，由粘膜免疫反应缺陷引起 遗传易感个体的肠道细菌/真菌。超过160个易感基因座，特别是免疫 CARD9、NOD2/CARD15、IRGM和ATG16L1等反应基因与CD的发病风险有关 欧洲血统的人。以前的研究已经确定了不同的成员和丰富的 CD患者与健康对照组肠道真菌菌群的比较，推断肠道可能的作用 真菌菌群在CD发病中的作用越来越多的证据支持主要的镉易感性的作用 基因，CARD9在真菌抗原的处理和天然免疫中的作用。然而，目前还不清楚是否 携带主要的遗传风险等位基因与任何特定真菌物种在 直觉。在这项研究中，我们将调查真菌在主要携带者和非携带者之间是否存在差异。 CD易感等位基因，同时关注遗传同质的德系犹太人(AJ)人口，谁 与其他族裔/种族群体相比，CD的患病率最高。假设条件包括：1) 肠道真菌谱受CARD9或CLEC7A风险变异体携带和2)Cd风险在 AJ的种群可归因于肠道和宿主遗传学中真菌物种的独特组合。 为了验证这些假设，候选人将重复使用K01支持的来自AJ CD患者的招募样本 登记西奈山消化内科正在进行的IBD患者登记 纽约医学院，已经对主要的CD风险进行了基因分型。候选人还将重复使用 AJ对照，没有CD，从西奈山生物库招募，用于K01研究。我们将利用真菌ITS2 靶向扩增双末端深度测序技术与生物信息学和统计学方法 关于疾病状态和遗传风险，描述研究对象的肠道真菌生物群。通过研究 基因同质性更高的群体(AJ)，结合来自K01研究的微生物组数据，本R03 这项研究将试图更好地了解微生物-真菌-宿主基因的相互作用 与疾病的发病机制有关。这有助于构建全面的诊断工具，以确定 有可能发展成CD的人，以及为AJ CD患者开发新的个性化治疗方法。在……里面 此外，这个项目将有助于为候选人未来的职业生涯建立一个强大的多学科基础 在翻译研究方面。

Project Summary The candidate applies a R03 grant that will expand his K01 supported career development in clinical research to complement his multidisciplinary training in immunology, microbiology, genetics and epidemiology and enable him to advance his scientific career by investigating the role of the gut mycobiome in Crohn's disease (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/fungi in genetically susceptible individuals. Over 160 susceptibility loci, particularly immune response genes such as CARD9, 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 mycobiota in CD patients compared with healthy controls, inferring a possible role of the gut mycobiome in CD pathogenesis. Accumulating evidence supports the role of the major CD susceptibility genes, CARD9 in the processing of fungal antigens and innate immunity. However, it is unclear whether carriage of the major genetic risk alleles correlates with an abundance of any particular fungi species in the gut. In this study we will investigate whether fungi 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 fungi profile of the gut is moderated by the carriage of CARD9 or CLEC7A risk variants and 2) the CD risk in the AJ population is attributable to the unique combination of fungi species in the gut and host genetics. To test these hypotheses, the candidate will reuse the K01 supported recruited samples from AJ CD patients enrolled in an ongoing registry 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. The candidate will also reuse the AJ controls without CD recruited from the Mount Sinai Biobank for the K01 study. We will utilize Fungal ITS2 targeted-amplicon pair-end deep sequencing technique followed by bioinformatics and statistical approaches to characterize the gut mycobiota in study subjects with regard to disease status and genetic risks. By studying a more genetically homogeneous population (AJ), combining the microbiome data from the K01 study, this R03 study will attempt to gain a better understanding of the microbiome-mycobiome-host gene interaction associated with disease pathogenesis. This can help build comprehensive diagnostic tools to identify individuals at risk of developing CD, as 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.