Impact of Genetic Variability on Cellular Pathways and Host-Microbiome Interactio

描述(由申请人提供)：到目前为止，已知有100多个基因变异与炎症性肠病(IBD)有关。其中大多数已经通过全基因组关联研究(GWAS)进行了鉴定。个体基因研究中心(GRC)和集体NIDDK IBD遗传学联盟在过去十年中成功地互动，领导了许多这些发现。然而，尽管取得了重大进展，但仍不清楚这些变异中的绝大多数是如何导致IBD的。回答这些问题对于增进我们对IBD病理生理学的认识至关重要。由Mark Silverberg博士领导的多伦多大学GRC凭借其在IBD方面的长期临床和遗传学专业知识，在这一领域做出了独特和实质性的贡献。自2002年以来，Silverberg博士在西奈山医院建立了一个非常大的、全面的登记，记录了具有良好特征的纵向跟踪的IBD患者，以及储存在他位于Samuel Lunenfeld研究所的实验室中的配套生物标本，以促进对IBD的研究。利用这些资源，UTGRC将通过以下方式促进对IBD病理生理学的理解：(1)识别有助于IBD分类和揭示在IBD病理生理学中具有机械重要性的基因表达谱和途径。这将通过测量受感染患者和健康对照的肠道组织中的基因表达谱来实现。(2)评估宿主遗传变异与肠道微生物群之间的相互作用，并确定这些变化对IBD表型表达的影响。这将通过确定附着在患者和健康对照组肠道组织上的微生物菌群的组成来实现。(3)继续以互动的方式与联盟成员合作，以完成与IBD相关的所有基因变异的发现，并促进我们对该等基因变异的功能生物学的了解，以便我们将改变受IBD影响的个人的结局。这将通过正在进行的临床患者和生物制品招募以及为联盟团队带来重要的临床和科学专业知识来实现。

DESCRIPTION (provided by applicant): To date more than 100 genetic variants are known to be associated with inflammatory bowel disease (IBD). The majority of these have been identified by genome-wide association studies (GWAS). The individual Genetic Research Centers (GRCs) and the collective NIDDK IBD Genetics Consortium have successfully interacted for the last ten years to lead many of these discoveries. However, despite significant progress it is still unknown how the vast majority of these variants lead to IBD. Answering these questions is critical to advancing our knowledge of IBD pathophysiology. The University of Toronto GRC, led by Dr. Mark Silverberg, has made unique and substantial contributions in this field by virtue of its longstanding clinical and genetics expertise in IBD. Since 2002, Dr. Silverberg has established a very large, comprehensive registry of well characterized, longitudinally followed IBD patients at Mount Sinai Hospital in addition to accompanying biospecimens stored at his laboratory at the Samuel Lunenfeld Research Institute in order to facilitate research in IBD. Utilizing these resources, the UTGRC will advance the understanding of IBD pathophysiology in the following ways: (1) To identify gene expression profiles and pathways that will aid in classifying IBD and in revealing those that are mechanistically important in IBD pathophysiology. This will be accomplished by measuring gene expression profiles in the intestinal tissue of those affected and of healthy controls. (2) To evaluate the interaction between host genetic variation and the intestinal microbiome and determine how these changes affect the phenotypic expression of IBD. This will be accomplished by determining the composition of the microbial flora adherent to the intestinal tissue of those affected and of healthy controls. (3) To continue to work in an interactive fashion with the members of the Consortium to complete the discovery of all genetic variation associated with IBD and to advance our knowledge of the functional biology of such genetic variation such that we will effect change in the outcomes of individuals affected by IBD. This will be accomplished by ongoing clinical patient and biospecimen recruitment and by bringing significant clinical and scientific expertise to the Consortium team.