Genomic and Immunologic Characterization of Inflammatory Bowel Disease and its Phenotypes

炎症性肠病及其表型的基因组和免疫学特征

• 批准号: 10543360
• 负责人: MARK S. SILVERBERG
• 金额: --
• 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 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543360
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Architecture; Back; Biological; Biological Response Modifier Therapy; Biology; Cells; Characteristics; Cities; Clinical; Clinical assessments; Colectomy; Colonic inflammation; Colorectal Cancer; Colorectal Neoplasms; Communities; Complement; Complication; Crohn' s disease; Cultural Diversity; Cytometry; Data; Development; Disease; Dysplasia; Etiology; Event; Flare; Functional disorder; Future; Genetic; Genetic Diseases; Genetic Research; Genetic Variation; Genetic study; Genomics; Goals; Histologic; Hospitalization; Hospitals; Image; Immune; Immunologic Factors; Immunologics; Individual; Inflammation; Inflammatory Bowel Diseases; Infrastructure; Intestines; Knowledge; Laboratories; Lead; Microscopic; Minority Groups; Molecular; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Neoplasms; North America; Outcome; Patient Care; Patients; Pattern; Phenotype; Population; Positioning Attribute; Prevalence; Quality of life; Recurrence; Recurrent disease; Refractory; Registries; Relapse; Research; Research Institute; Resources; Retrospective cohort; Risk; Risk Factors; Sampling; Series; Structure; Susceptibility Gene; Techniques; Technology; Therapeutic Intervention; Time; Tissues; Translations; Ulcerative Colitis; Underrepresented Populations; Universities; Variant; Work; chronic inflammatory disease; clinical care; clinical risk; colitis-associated neoplasia; colorectal cancer risk; disease phenotype; effective therapy; genetic architecture; genetic variant; genome wide association study; genomic profiles; improved; improved outcome; insight; microbial; microbial genomics; microbiome; microbiome analysis; mortality; multiple omics; overtreatment; patient population; patient response; prevent; prospective; relapse risk; single-cell RNA sequencing; tool; transcriptomics

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 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. 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 to facilitate research in IBD. Utilizing these resources and applying new expertise in cellular, genomic and immune profiling, it is anticipated that the proposed studies will help to make significant progress in the unmet needs described above. The IBDGC working together with the UTGRC will study comprehensively the genetic architecture of non-European ancestry IBD populations and utilize the power of its infrastructure to better elucidate the pathophysiology of acute severe ulcerative colitis and perianal Crohn’s disease. The UTGRC, specifically, will advance the understanding of UC pathophysiology by integrating imaging mass cytometry, spatial transcriptomics and scRNA-seq, in conjunction with tissue-associated microbiome analysis, to develop a comprehensive understanding of the immune, genomic, cellular and microbial factors that contribute to persistent histologic inflammation and mechanisms of clinical relapse in UC. Utilizing the power of these technologies, also provides a unique opportunity to go “back in time” to study critical events that lead to the development of colorectal cancer in UC – a poorly understood complication with significant mortality. By applying similar techniques in a retrospective cohort, the cellular and immune factors that lead to treatment refractory CD. Despite the progress in advanced biologic therapy, there are still a significant portion of patients who fail multiple therapies and have persistent inflammation. Taken together, through the studies proposed, it is anticipated that significant advances will be made toward better understanding the functional biology of IBD genetic variation and to enable the translation of these data to clinically meaningful tools that will lead improved outcomes for individuals affected by IBD.

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。 其中大多数已经通过全基因组关联研究(GWAS)进行了鉴定。个人 基因研究中心(GRC)和集体NIDDK IBD遗传学联盟已成功 在过去的15年里，他们相互作用，引领了其中的许多发现。然而，尽管取得了重大进展，但它 目前仍不清楚大多数这些变异或其他危险因素是如何导致IBD及其两个 主要亚型-克罗恩病(CD)和溃疡性结肠炎(UC)。回答这些问题对于 提高我们对IBD病理生理学的认识。 自2002年以来，西尔弗伯格博士已经建立了一个非常大的、全面的登记， 在西奈山医院对IBD患者进行了纵向跟踪调查，并储存了随行的生物样本 他在鲁南菲尔德-塔南鲍姆研究所的实验室里，为IBD的研究提供便利。利用这些 资源，并应用细胞、基因组和免疫图谱方面的新专业知识，预计 拟议的研究将有助于在上述未得到满足的需求方面取得重大进展。IBDGC 与UTGRC合作，将全面研究非欧洲人的遗传结构 并利用其基础设施的力量更好地阐明IBD的病理生理学 急性严重溃疡性结肠炎和肛周克罗恩病。具体地说，UTGRC将推进 结合成像质谱仪、空间转录学和电子显微镜对UC病理生理的认识 ScRNA-seq，结合组织相关微生物组分析，开发一种全面的 了解免疫、基因组、细胞和微生物因素对持久组织学的影响 UC的炎症反应和临床复发机制。利用这些技术的力量，还 提供了一个独特的机会，可以追溯到过去，研究导致 UC中的结直肠癌--一种鲜为人知的并发症，死亡率很高。通过应用类似的 技术回顾队列，细胞和免疫因素，导致治疗难治性CD。 尽管先进的生物疗法取得了进步，但仍有相当一部分患者失败。 有多种治疗方法，并有持续性炎症。总而言之，通过提出的研究，它是 预计将在更好地理解IBD的功能生物学方面取得重大进展 并使这些数据能够转化为具有临床意义的工具，从而使 受IBD影响的个人的结局。