Elucidating Pathophysiological Mechanisms of Intestinal Inflammation

项目总结/摘要 迄今为止，已知有200多种遗传变异与炎症性肠病（IBD）相关。的 其中大多数已通过全基因组关联研究（GWAS）鉴定。个体基因 研究中心（GRC）和集体NIDDK IBD遗传学联盟成功地互动， 在过去的15年里，他领导了许多这样的发现。然而，尽管取得了重大进展， 绝大多数这些变异或其他风险因素如何导致IBD及其两种主要亚型的发展 - 克罗恩病（CD）和溃疡性结肠炎（UC）。解决这些问题对于推进我们的 IBD病理生理学知识。 由Mark Silverberg博士领导的多伦多大学GRC在以下方面做出了独特而实质性的贡献： 凭借其在IBD方面长期的临床和遗传学专业知识，自2002年以来，西尔弗伯格博士 建立了一个非常大的，全面的登记，充分表征，纵向随访IBD患者， 西奈山医院除了在他位于卢嫩菲尔德的实验室储存的生物标本外， Tanenbaum研究所，以促进IBD的研究。利用这些资源，UTGRC将 通过以下方式推进对UC病理生理学的理解：（1）确定基因表达谱 以及有助于理解UC复发机制和预测UC复发的途径， 它们通过miRNAs和染色质可及性进行调节。这将通过测量基因 在UC受试者的结肠组织中的miRNA表达、miRNA和染色质可及性概况， 相对于基线测量的炎症发作。(2)确定肠道微生物和微生物 UC复发前的功能。这将通过确定微生物的组成来实现。 粘附于肠组织的植物群以及在相同时间点采集并比较的粪便中的菌群 在（1）中描述。(3)继续支持共同商定的全联合体研究， 导致CD受试者手术后炎症复发的因素，完成了 所有与IBD相关的遗传变异，推进我们对这种遗传变异的功能生物学的认识。 变化，并利用这些数据，使临床上有意义的工具投入使用，以促进改善结果， 受IBD影响的人。这些将通过招募患者和将我们的重要 为IBDGC提供临床和科学专业知识。这将由正在进行的临床患者完成， 生物标本的招募，并带来重要的临床和科学专业知识的联盟团队。

Project Summary/Abstract To date more than 200 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 fifteen years to lead many of these discoveries. However, despite significant progress it is still unknown how the vast majority of these variants or other risk factors lead to development of IBD and its two major subtypes - Crohn’s disease (CD) and ulcerative colitis (UC). 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 Lunenfeld- Tanenbaum Research Institute in order to facilitate research in IBD. Utilizing these resources, the UTGRC will advance the understanding of UC pathophysiology in the following ways: (1) Identify gene expression profiles and pathways that will aid in understanding the mechanisms of UC relapse and prediction of UC relapse and their regulation by miRNAs and chromatin accessibility. This will be accomplished by measuring gene expression, miRNA and chromatic accessibility profiles in the colonic tissue of UC subjects immediately prior to the onset of inflammation relative to baseline measurements. (2) Identify intestinal microbes and microbial function that precede UC relapse. This will be accomplished by determining the composition of the microbial flora adherent to the intestinal tissue as well as that of stool sampled at and comparing the same time points described in (1). (3) Continue to support the mutually agreed upon Consortium-wide studies involving elucidating the factors contributing to relapse of inflammation following surgery in CD subjects, completing the discovery of all genetic variation associated with IBD, advancing our knowledge of the functional biology of such genetic variation and to utilize these data to bring clinically meaningful tools into use to promote improved outcomes for individuals affected by IBD. These will be accomplished by patient recruitment and by bringing our significant clinical and scientific expertise to the IBDGC. This will be accomplished by ongoing clinical patient and biospecimen recruitment and by bringing significant clinical and scientific expertise to the Consortium team.