Text Image: UM Medical School: Graduate Program in Immunology
Text Image: Faculty

Joseph Holoshitz, M.D.
Professor of Internal Medicine
Associate Chief for Research

Division of Rheumatology

Research Interests

The research theme of Dr. Holoshitz' laboratory is the role of signal transduction events in health and disease. Using cellular, molecular, signal transduction and protein chemistry strategies, the laboratory is focusing on three research projects:

1. We have recently discovered that the rheumatoid arthritis (RA) shared epitope (SE) is capable of altering important signaling events. The cell surface receptor of the SE has been identified. We are presently characterizing the intracellular events that the SE triggers and deciphering the structure/function requirements of ligand-receptor interaction, using empiric and combinatorial peptide design approaches as well as mutational analysis of the binding domain(s) on the receptor. In a related project, the effect of the SE on osteoclast activation and differentiation is being studied. Beyond their potential utility for understanding mechanisms in RA, these studies could provide new insights into MHC-disease association.

2. Using rational design, as well as iterative compound screening techniques, we have identified several lead compounds that competitively inhibit SE interaction with its receptor, and block activation of SE signaling. When administered to mice, these leads ameliorate experimental arthritis. The medicinal properties of these leads are now being studied with intent to optimize their bioavailability and biostability.

3. RA susceptibility and disease severity have been previously found to be affected by both genetic and environmental factors, but the mechanisms underlying these risk factors and the interactions between them remain unknown. We have recently identified a candidate molecular basis for gene-environment interaction in RA. Current research efforts are aimed at mapping the respective pathways, determining the molecular basis for the observed interaction between the two pathways, and analyzing differential transcriptomes induced by activation of these pathways, both individually and in combination.

Representative Publications

Haas, C, Creighton CJ, Pi X, Maine I, Koch EA, Haines GK III, Ling S, Chinnaiyan AM and Holoshitz J. Identification of genes modulated in rheumatoid arthritis using cDNA microarray analysis of disease-discordant monozygotic twin cells. Arthritis Rheum. 54: 2047-2060, 2006.

Ling S, Lai A, Borschukova O, Pumpens P and Holoshitz J. Activation of nitric oxide signaling by the rheumatoid arthritis shared epitope. Arthritis Rheum. 54, 3423-3432, 2006.

Tan SY, Xiao L, Pi X and Holoshitz J. Aberrant Gi protein-coupled receptor-mediated cell survival signaling in rheumatoid arthritis B cell lines. Frontiers in Bioscience, 12, 1651-1660, 2007.

Ling S, Li Z, Borschukova O, Xiao L, Pumpens P, and Holoshitz J. The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway. Arthritis Res. Therapy. 9, R5, 2007.

Holoshitz J and Ling S. Nitric oxide signaling triggered by the rheumatoid arthritis shared epitope: a new paradigm for MHC-disease association? Ann New York Acad Sci, 1 110:73-83, 2007.

Ling S, Pi X and Holoshitz J. The rheumatoid arthritis shared epitope triggers innate immune signaling via cell surface calreticulin. J Immunol. 179:6359-6367, 2007.

Holoshitz J. The rheumatoid arthritis HLA-DRB1 shared epitope. Current Opinion in Rheumatology, 22:293-298, 2010.

De Almeida DE, Ling S, Pi X, Hartmann-Scruggs AM, Pumpens P and Holoshitz J. Immune dysregulation by the rheumatoid arthritis shared epitope. J Immunol. 185: 1927-34, 2010.

Holoshitz J, De Almeida DE and Ling S. A role of calreticulin in the pathogenesis of rheumatoid arthritis. Ann New York Acad Sci.1209:91-8, 2010.

Ling S, Cheng A, Pumpens P, Michalak M and Holoshitz J. Identification of the Rheumatoid Arthritis Shared Epitope Binding Site on Calreticulin. PlosONE. 5:11703, 2010.

De Almeida DE, Holoshitz J. MHC molecules in health and disease: At the cusp of a paradigm shift. Self Nonself. 2:43-8, 2011.

De Almedia DE, Ling S, Holoshitz, J. New insights into the functional role of the rheumatoid arthritis shared epitope. FEBS Lett. 2011 Mar 22. [Epub ahead of print].

De Almedia DE, Ling S, Holoshitz, J. New insights into the functional role of the rheumatoid arthritis shared epitope. FEBS Letters 585(23):3619-26, 2011

Naveh S, Tal-Gan Y, Ling S, Hoffman A, Holoshitz J, Gilon, C. Developing potent backbone cyclic peptides bearing the shared epitope sequence as rheumatoid arthritis drug-leads. Bioorg & Medicinal Chem Lett 22(1):493-6, 2012.

Holoshitz J, Liu Y, Fu J, Joseph J, Ling S, Colletta A, Sharma P, Begun D, Goldstein S, Taichman R. An HLA-DRB1-Coded Signal Transduction Ligand Facilitates Inflammatory Arthritis. A New Mechanism of Autoimmunity. J. Immunol. 190:48-57, 2013.

Ling S, Cline EN, Haug T, Fox DA, Holoshitz J. Citrullinated calreticulin potentiates rheumatoid arthritis shared epitope signaling. Arthritis Rheum. 65:618-26, 2013.

Fu J, Ling S, Liu Y, Yang J, Naveh S, Hannah M, Gilon C, Zhang Y, Holoshitz J. A small shared epitope-mimetic compound potently accelerates osteoclast-mediated bone damage in autoimmune arthritis. J Immunol. 191:2096-103, 2013.

Blanco LP, Plegue M, Fung-Leung W-P, Holoshitz J. Gender-biased regulation of human IL-17-producing cells in vitro by peptides corresponding to distinct HLA-DRB1 allele-coded sequences. Journal of Immune Based Therapies, Vaccines and Antimicrobials 2:29-38, 2013.

Holoshitz J. The quest for better understanding of HLA-disease association: scenes from a road less travelled by. Discovery Medicine. 16:93-102, 2013.

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