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

描述（由申请人提供）：迄今为止，已知有100多种遗传变异与炎症性肠病（IBD）相关。其中大多数已通过全基因组关联研究（GWAS）确定。个体遗传研究中心（GRCs）和集体NIDDK IBD遗传联盟在过去十年中成功地进行了互动，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绝大多数是如何导致IBD的。回答这些问题对于提高我们对IBD病理生理学的认识至关重要。多伦多大学GRC由Mark Silverberg博士领导，凭借其在IBD方面的长期临床和遗传学专业知识，在该领域做出了独特而实质性的贡献。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、具有良好特征的、纵向跟踪的IBD患者登记册，此外还在Samuel Lunenfeld研究所的实验室中储存了生物标本，以促进IBD的研究。利用这些资源，UTGRC将通过以下方式促进对IBD病理生理的理解：(1)识别有助于IBD分类的基因表达谱和途径，并揭示那些在IBD病理生理中具有重要机械意义的基因表达谱和途径。这将通过测量受影响者和健康对照者肠道组织中的基因表达谱来完成。(2)评估宿主遗传变异与肠道微生物组的相互作用，并确定这些变化如何影响IBD的表型表达。这将通过确定附着在受影响者和健康对照者肠道组织上的微生物菌群的组成来完成。(3)继续以互动的方式与联盟成员合作，完成与IBD相关的所有遗传变异的发现，并推进我们对这种遗传变异的功能生物学知识，从而影响IBD患者预后的改变。这将通过持续的临床患者和生物标本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. PUBLIC HEALTH RELEVANCE: The University of Toronto Genetic Research Center, working within the NIDDK IBD Genetics Consortium, is proposing a series of projects aimed at fully identifying all of the genetic factors that lead to an inherited predisposition to inflammatory bowl disease (IBD). UTGRC will also investigate how patients with these susceptibility factors actually develop IBD by incorporating studies examining how genes are expressed and the composition of the bacteria in the digestive tract. By understanding these processes the aim is to prevent individuals from developing IBD and to improve the quality of life of those individuals currently affected.