Elucidating Pathophysiological Mechanisms of Intestinal Inflammation

项目摘要/摘要 到目前为止，已知有200多个基因变异与炎症性肠病(IBD)有关。这个 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遗传学联盟成功地为 在过去的15年里领导了许多这样的发现。然而，尽管取得了重大进展，但仍不得而知。 绝大多数这些变异或其他危险因素如何导致IBD及其两个主要亚型的发展 -克罗恩病(CD)和溃疡性结肠炎(UC)。回答这些问题对于推进我们的 具备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重大的贡献 这一领域凭借其在IBD方面的长期临床和遗传学专业知识。自2002年以来，西尔弗伯格博士一直 建立了一个非常大的、全面的登记，登记了特征良好的纵向跟踪的IBD患者，地址为 西奈山医院除了随行储存在他在卢恩菲尔德的实验室里的生物标本外- Tanenbaum研究所，以促进对IBD的研究。利用这些资源，UTGRC将 从以下几个方面促进对UC病理生理学的理解：(1)鉴定基因表达谱 以及有助于了解UC复发机制和UC复发和预测的途径 它们受miRNAs和染色质可及性的调节。这将通过测量基因来完成 溃疡性结肠炎患者治疗前结肠组织表达、miRNA和染色可及性 相对于基线测量的炎症发作。(2)鉴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。 在同一时间点采样并比较肠道组织和粪便上附着的菌群 第(1)项所述。(3)继续支持双方商定的涉及澄清的财团范围研究 CD患者手术后炎症复发的因素，完成了对 所有与IBD相关的基因变异，促进了我们对这些基因的功能生物学的了解 并利用这些数据将临床上有意义的工具投入使用，以促进改善预后 受IBD影响的个人。这些将通过招募患者和为我们带来重要的 向IBDGC提供临床和科学方面的专业知识。这将由持续的临床患者和 通过招募Biospecimen，并为联盟团队带来重要的临床和科学专业知识。

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.