Elucidating Pathophysiological Mechanisms of Intestinal Inflammation

阐明肠道炎症的病理生理机制

• 批准号: 9401387
• 负责人: MARK S. SILVERBERG
• 金额: $ 31.2万
• 依托单位: SINAI HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401387
• 关键词: Achievement; Adopted; Adrenal Cortex Hormones; Affect; Anti-Tumor Necrosis Factor Therapy; Biology; Chromatin; Clinical; Colectomy; Complement; Crohn' s disease; Data; Development; Disease; Disease remission; Epigenetic Process; Feces; Flare; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Research; Genetic Variation; Goals; Hereditary Disease; Heritability; Hospitalization; Hospitals; Human; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Knowledge; Laboratories; Lead; Measurement; Measures; Medical Genetics; Messenger RNA; MicroRNAs; Microbe; Modeling; Molecular Profiling; Mucositis; National Institute of Diabetes and Digestive and Kidney Diseases; Operative Surgical Procedures; Pathway interactions; Patient Recruitments; Patients; Postoperative Period; Predisposition; Process; Prognostic Marker; Progress Reports; Quality of life; Recruitment Activity; Recurrence; Registries; Regulation; Relapse; Reporting; Research; Research Institute; Resources; Risk; Risk Factors; Sampling; Series; Structure; Symptoms; Therapeutic; Time; Tissues; Ulcerative Colitis; Universities; Variant; Work; adverse outcome; clinical risk; colon dysplasia; disorder risk; experimental study; genetic variant; genome wide association study; gut microbiome; healing; improved; improved outcome; mRNA Expression; microbial; microbiome; relapse prediction; relapse risk; risk variant; tool

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.

项目概要/摘要 迄今为止，已知超过 200 种遗传变异与炎症性肠病 (IBD) 相关。这 其中大部分已通过全基因组关联研究（GWAS）确定。个体遗传 研究中心 (GRC) 和 NIDDK IBD 遗传学联盟已成功进行互动 过去十五年来引领了许多这样的发现。然而，尽管取得了重大进展，但仍然未知 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）。回答这些问题对于推动我们的发展至关重要 IBD 病理生理学知识。 由 Mark Silverberg 博士领导的多伦多大学 GRC 在以下领域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，在这一领域取得了巨大的成功。自 2002 年以来，西尔弗伯格博士 建立了一个非常大、全面的、特征明确、纵向随访的 IBD 患者登记处 西奈山医院除了存储在他位于 Lunenfeld 的实验室中的生物样本外， Tanenbaum 研究所旨在促进 IBD 的研究。 UTGRC 将利用这些资源 通过以下方式增进对 UC 病理生理学的理解： (1) 识别基因表达谱 以及有助于了解 UC 复发机制和预测 UC 复发的途径 它们受 miRNA 和染色质可及性的调节。这将通过测量基因来完成 UC 受试者结肠组织中的表达、miRNA 和染色可及性概况 相对于基线测量的炎症发作。 (2) 肠道微生物及微生物的鉴定 UC 复发前的功能。这将通过确定微生物的组成来实现 粘附在肠道组织上的菌群以及在同一时间点采样的粪便中的菌群并进行比较 (1)中描述。 (3) 继续支持双方商定的联盟范围内的研究，包括阐明 导致 CD 受试者手术后炎症复发的因素，完成了以下发现 与 IBD 相关的所有遗传变异，提高了我们对此类遗传功能生物学的了解 变化并利用这些数据将具有临床意义的工具投入使用，以促进改善结果 受 IBD 影响的个人。这些将通过患者招募和带来我们重要的 向 IBDGC 提供临床和科学专业知识。这将通过持续的临床患者和 生物样本招募以及为联盟团队带来重要的临床和科学专业知识。