Epigenomics of Systemic Autoimmunity

描述（由申请人提供）：本申请的总体目标是建立一个程序，该程序有助于将淋巴细胞生物学中的开创性表观遗传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。这将通过本提案中描述的相互关联的项目促进在基础和临床研究前沿工作的研究者之间的合作来实现。该应用程序汇集了密歇根大学（UM）的广泛资源，科学人才和临床专业知识，以创建一个自身免疫卓越中心（ACE），与其他机构的合作自身免疫卓越中心一起，将增强对自身免疫性疾病的理解，包括系统性红斑狼疮，以及类风湿性关节炎，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础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/翻译项目集中在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方法和技术来表征外源性表观遗传修饰剂对T细胞表观基因组和基因表达的影响，这些表观基因组和基因表达在系统性红斑狼疮患者以及其他形式的系统性自身免疫中发现的以前未描述的T细胞亚群中。这些研究还将使用体外试验鉴定和测试这些研究中鉴定的新治疗靶点。试点项目将比较该亚组患者与其他活性和 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 自身免疫性肝病以及这些患者中亚组与表观遗传学相关环境暴露的生物标志物的关系。该合作项目将定义新型T细胞亚群大小，总狼疮遗传风险和非活动性和活动性狼疮患者的SLEDAI评分之间的关系，并在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。

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.