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.
The treatment of human lupus still relies on nonspecific cytotoxic drugs with incomplete effectiveness and significant side effects. Understanding the mechanisms causing lupus and related diseases will likely lead to new and better therapies. The studies described in this proposal will use state-of-the-art genomic and epigenomic approaches to uncover novel aspects in lupus pathogenesis, identify new therapeutic targets, investigate epigenetic-environmental interaction, and test a novel biomarker for disease progression in lupus.