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University of Michigan Clinical Autoimmunity Center of Excellence

密歇根大学临床自身免疫卓越中心

基本信息

批准号：
10165485
负责人：
David Alan Fox
金额：
$ 7.8万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165485
关键词：
Activated-Leukocyte Cell Adhesion Molecule Autoimmune Autoimmune Diseases Autoimmunity Biological Cells Clinical Clinical Research Clinical Trials Clinical effectiveness Collaborations Core Facility Cutaneous Development Disease Disease Pathway Doctor of Philosophy Evolution Faculty Fibrosis Fostering Foxes Funding Future Generations Home Host Defense Human Immune system Immunologics Immunosuppressive Agents Impairment Inflammation Institution Interferons Janus kinase Lead Leadership Link Lupus Lymphocyte Lymphocyte Subset Mediating Michigan Molecular Molecular Target Multiple Sclerosis National Institute of Allergy and Infectious Disease Organ Pathogenesis Pathogenicity Patients Pharmaceutical Preparations Photosensitivity Play Population Principal Investigator Process Productivity Proteins Protocols documentation Reagent Research Personnel Rheumatoid Arthritis Role Sampling Scientist Scleroderma Skin Stromal Cells Systemic Lupus Erythematosus Systemic Scleroderma Translational Research Universities Validation Work Yang alanine aminopeptidase autoimmune inflammation autoimmune rheumatologic disease autoimmune thyroid disease base biobank clinical predictors cohort cytotoxic effective therapy experience individual patient insight keratinocyte kinase inhibitor novel novel marker novel strategies patient subsets personalized medicine programs targeted treatment trial design

项目摘要

Abstract The current work of the University of Michigan Clinical ACE is built on the hypothesis that organ- targeted autoimmune diseases depend on unique pathogenic interactions between cells of the immune system and parenchymal or stromal cells of the target organ, both in disease initiation and target organ destruction. Based on advances over the past five years, we propose here a new but related central hypothesis, that novel, safer and more effective precision-targeted and personalized therapies for autoimmune diseases can be developed based on insights into two critical and interacting components of autoimmune diseases: 1) the molecular mechanisms by which target organ stromal and parenchymal cells initiate, orchestrate and control the evolution and consequences of autoimmune diseases and 2) the critical roles of localization of unusual lymphocyte populations to target organs in subsets of patients with autoimmune diseases, and the opportunity for elimination of these cells without substantial impairment of normal host defenses. The primary clinical project, CD319 as a novel target for treatment of systemic sclerosis: Treatment with Elotuzumab, led by Dinesh Khanna, MD, MSc is built on evidence for a pathogenic role of CD4+CD319+ lymphocytes in autoimmune diseases that leads to fibrosis of target organs. We believe that this will be the first protocol to select subjects for treatment of a human autoimmune disease based on demonstration of expansion of the targeted lymphocyte subset at trial entry. The alternate clinical project: Tofacitinib for treatment of photosensitivity and cutaneous inflammation in systemic lupus, led by J. Michelle Kahlenberg, MD, PhD, is based on our observation that keratinocyte-derived interferon-kappa drives photosensitivity and cutaneous inflammation in lupus skin. Treatment of these aspects of lupus with a janus kinase inhibitor will be a step towards more precise targeting of interferon-kappa in lupus. Our collaborative project: Validation of novel molecular targets for more precise treatment of autoimmune diseases, led by David A. Fox, MD, will assess expression and function of selected molecules produced by stromal cells in target organs of a broad range of autoimmune diseases -- AIRE (the autoimmune regulator protein), CD318 (a novel ligand of CD6) and CD13, which may have major pathogenic roles in human autoimmune conditions. These projects will be supported by an Administrative Core and a Funds Management Core, and by numerous patient cohorts, disease-focused clinical programs, core facilities and biorepositories at the University. The Principal Investigators, Drs. Dinesh Khanna and David A. Fox, work in close collaboration on our existing Clinical ACE and have substantial experience and productivity in clinical and translational research in systemic sclerosis, rheumatoid arthritis and other human rheumatic/autoimmune diseases. Together with a team of colleagues at the University of Michigan and future collaborators from other ACE institutions, this group of investigators is poised to make valuable contributions to our understanding and treatment of autoimmune diseases.

摘要