Epigenomics of Systemic Autoimmunity

系统性自身免疫的表观基因组学

• 批准号: 8680684
• 负责人: BRUCE C. RICHARDSON
• 金额: $ 69.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680684
• 关键词: Adverse effects; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Basic Science; Biological Markers; Cells; Clinical; Clinical Research; Collaborations; Cytotoxic agent; Development; Diagnostic; Disease; Disease Progression; Disease remission; Effectiveness; Environment; Environmental Exposure; Epigenetic Process; Gene Expression; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genomics; Goals; Human; Hydralazine; Immune system; Immunology; Inherited; Institution; Invaded; Lead; Liver diseases; Longitudinal Studies; Lupus; Lymphocyte Biology; Michigan; Monozygotic twins; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Pilot Projects; Procainamide; Prognostic Marker; Proteins; Reporting; Research Personnel; Resources; Rheumatoid Arthritis; Scleroderma; Self Tolerance; Sjogren' s Syndrome; Susceptibility Gene; Systemic Lupus Erythematosus; Systemic Scleroderma; T-Lymphocyte; T-Lymphocyte Subsets; Talents; Technology; Testing; Tissues; Translations; Universities; Work; design; drug induced lupus; drug metabolism; environmental agent; epigenome; epigenomics; in vitro Assay; insight; lupus-like; new therapeutic target; novel; novel strategies; pathogen; programs; therapeutic target

DESCRIPTION (provided by applicant): The overall goal of this application is to establish a program that facilitates translation of groundbreaking epigenetic concepts in lymphocyte biology and their interaction with genetic predisposition into new approaches to the treatment of human autoimmune diseases. This will be achieved by facilitating collaborations between investigators working at the forefront of basic and clinical research through the interconnected projects described in this proposal. This application brings together the extensive resources, scientific talent and clinical expertise at the University of Michigan (UM) to create an Autoimmunity Center of Excellence (ACE) that, together with the collaborating Autoimmunity Centers of Excellence at other institutions, will enhance understanding of autoimmune diseases including systemic lupus erythematosus, as well as rheumatoid arthritis, scleroderma, Sjogren's Syndrome and autoimmune liver diseases. The UM-ACE proposal unites basic groups studying mechanisms of epigenetics and lymphocyte biology with clinical researchers studying the immunology and treatment of these autoimmune diseases. The three basic/translational projects focus on genetic/epigenetic interactions in the development of autoimmunity, and are designed to identify novel mechanisms for targeted therapy. The Principal Project will use state of the art genomic and epigenomic approaches and technology to characterize the impact of exogenous epigenetic modifiers on the T cell epigenome and gene expression in a previously undescribed T cell subset found in patients with systemic lupus erythematosus as well as other forms of systemic autoimmunity. These studies will also identity and test novel therapeutic targets identified in these studies, using in vitro assays. The Pilot Project will compare the size of this subset in patients with other active and inactive autoimmune diseases, including rheumatoid arthritis, scleroderma, Sjogren's Syndrome and autoimmune liver diseases as well as the relationship of the subset to biomarkers of epigenetically relevant environmental exposures in these patients. The collaborative project will define the relationship between the novel T cell subset size, total lupus genetic risk, and the SLEDAI score in patients with inactive and active lupus, and test the presence and size of the subset as a prognostic biomarker for disease progression and remission in a multicenter longitudinal study.

描述(由申请人提供)：本申请的总体目标是建立一个计划，促进将淋巴细胞生物学中突破性的表观遗传学概念及其与遗传易感性的相互作用转化为治疗人类自身免疫性疾病的新方法。这将通过促进处于基础和临床研究前沿的研究人员之间的合作来实现，通过本提案中描述的相互关联的项目。这项申请汇集了密歇根大学(UM)的广泛资源、科学人才和临床专业知识，创建了一个自动免疫卓越中心(ACE)，该中心与其他机构的自动免疫卓越中心合作，将加强对自身免疫性疾病的了解，包括系统性红斑狼疮、类风湿性关节炎、硬皮病、干燥综合征和自身免疫性肝病。UM-ACE提案将研究表观遗传学和淋巴细胞生物学机制的基本小组与研究这些自身免疫性疾病的免疫学和治疗的临床研究人员联合起来。这三个基本/翻译项目侧重于自身免疫发展中的遗传/表观遗传相互作用，旨在确定靶向治疗的新机制。主要项目将使用最先进的基因组和表观基因组学方法和技术来表征外源性表观遗传学修饰物对系统性红斑狼疮和其他形式的系统性自身免疫患者的T细胞表观基因组和以前未描述的T细胞亚群的基因表达的影响。这些研究还将使用体外试验来确定和测试在这些研究中确定的新的治疗靶点。该试点项目将比较这一亚群患者与其他活动和 非活动性自身免疫性疾病，包括类风湿性关节炎、硬皮病、干燥综合征和 这些患者的自身免疫性肝病及其亚群与表观遗传相关环境暴露生物标记物的关系。这项合作项目将确定新的T细胞亚群大小、狼疮总遗传风险和活动期狼疮患者的SLEDAI评分之间的关系，并在一项多中心纵向研究中测试该亚群的存在和大小作为疾病进展和缓解的预后生物标志物。