A New Treatment Paradigm for Human Leukocyte Antigen (HLA)-Associated Diseases The proposed project will build the foundation of a new interdisciplinary team consisting of 2 independent laboratories: a UM Medical School group headed by Joseph Holoshitz, MD, whose longstanding focus has been on the pathobiology of rheumatoid arthritis (RA), and a group at the UM College of Pharmacy, headed by Henry Mosberg, PhD, an expert in medicinal chemistry. The 2 teams will join efforts to rationally design new therapeutic compounds for RA, based on a highly innovative concept, discussed briefly below. Under the parent NIAMS-funded R01 grant, we have recently uncovered a novel mechanism of HLA- disease association, by showing that the single most important genetic risk factor for RA, a HLA-DRB1- coded sequence motif called 'shared epitope'(SE), is a signal transduction ligand that activates Th17 polarization and increases disease severity in experimental arthritis. Moreover, based on these data, we have rationally designed a prototypic small inhibitory molecule that exerts potent anti-arthritis therapeutic effects at pM-range doses. The long-term goal of the new collaboration is to establish the foundations on which multidisciplinary teams of investigators will be able to design new therapeutic agents for HLA-associated diseases. The requested BIRT funds will be used to test-pilot the idea, focusing on RA. Based on the success of the proposed studies in RA, the program could be extended in the format of P01, or multi-PI R01s, to other HLA- associated conditions. Specifically, in the studies proposed here, we will: 1. Design compound analogs with improved bioavailability and decipher their conformation (Mosberg);2. Determine their membrane permeability and oral availability (Holoshitz);3. Determine the biologic effects of the new compounds both in vitro and in an experimental model of RA (Holoshitz). The project conforms well with the BIRT idea: It involves a newly formed interdisciplinary team from distinct scientific fields and schools;the underlying concept is highly novel;the project involves a high-risk/high yield research pursuit;it will examine a paradigm-changing theory, and;the proposed studies will build the foundations on which novel drugs could be developed in a wide-range of HLA-associated conditions.

Public Health Relevance

This project proposes a novel idea for design and development of a new class of drug for rheumatoid arthritis and other bone-destroying conditions. If successful, this approach could be adapted to many other autoimmune and inflammatory diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZAR1-KM (M1))
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Mao, Su-Yau
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Fu, Jiaqi; Ling, Song; Liu, Ying et al. (2013) A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis. J Immunol 191:2096-103
Ling, Song; Cline, Erika N; Haug, Timothy S et al. (2013) Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling. Arthritis Rheum 65:618-26
Holoshitz, Joseph; Liu, Ying; Fu, Jiaqi et al. (2013) An HLA-DRB1-coded signal transduction ligand facilitates inflammatory arthritis: a new mechanism of autoimmunity. J Immunol 190:48-57
Naveh, Shirly; Tal-Gan, Yftah; Ling, Song et al. (2012) Developing potent backbone cyclic peptides bearing the shared epitope sequence as rheumatoid arthritis drug-leads. Bioorg Med Chem Lett 22:493-6