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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI110502-01
Application #
8680684
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Johnson, David R
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gensterblum, Elizabeth; Renauer, Paul; Coit, Patrick et al. (2018) CD4+CD28+KIR+CD11ahi T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients. J Autoimmun 86:19-28
Ray, Donna; Strickland, Faith M; Richardson, Bruce C (2018) Oxidative stress and dietary micronutrient deficiencies contribute to overexpression of epigenetically regulated genes by lupus T cells. Clin Immunol 196:97-102
Richardson, Bruce (2018) The interaction between environmental triggers and epigenetics in autoimmunity. Clin Immunol 192:1-5
Weeding, Emma; Coit, Patrick; Yalavarthi, Srilakshmi et al. (2018) Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils. Clin Immunol 196:110-116
Alperin, Jessie M; Ortiz-Fernández, Lourdes; Sawalha, Amr H (2018) Monogenic Lupus: A Developing Paradigm of Disease. Front Immunol 9:2496
Strickland, F M; Mau, T; O'Brien, M et al. (2017) Oxidative T Cell Modifications in Lupus and Sjogren's Syndrome. Lupus (Los Angel) 2:
Dozmorov, Mikhail G; Coit, Patrick; Maksimowicz-McKinnon, Kathleen et al. (2017) Age-associated DNA methylation changes in naive CD4+ T cells suggest an evolving autoimmune epigenotype in aging T cells. Epigenomics 9:429-445
Teruel, Maria; Sawalha, Amr H (2017) Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies. Curr Rheumatol Rep 19:32
Tsou, Pei-Suen; Sawalha, Amr H (2017) Unfolding the pathogenesis of scleroderma through genomics and epigenomics. J Autoimmun 83:73-94
Strickland, Faith M; Patel, Dipak; Khanna, Dinesh et al. (2016) Characterisation of an epigenetically altered CD4(+) CD28(+) Kir(+) T cell subset in autoimmune rheumatic diseases by multiparameter flow cytometry. Lupus Sci Med 3:e000147

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