UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Innate immune cells are important sensors of their microenvironment and provide early responses to infectious, neoplastic and environmental stresses. Their effector functions are closely regulated through a balance of signals mediated through a variety of activating and inhibitory cell surface receptors. Our laboratory has focused on the study of receptors that regulate cells in the innate immune system. We have focused on receptors on natural killer cell lymphocytes until recently. We are now examining similar receptors on osteoclasts. These recent studies demonstrated that innate immune receptors are critical regulators of osteoclast development and function, thus osteoclasts should be considered an integral part of the innate immune system.

Our current studies focus on: (1) identification of receptors and their ligands in both NK cells and osteoclasts, (2) delineation of signaling pathways utilized by these receptors in specific cellular functions, and (3) determining the role of specific receptors in the regulation of immune responses, autoimmunity and bone remodeling. We are examining the roles of specific NK cell receptors in specific animal models involving immune-mediated tumor rejection and an established model for systemic lupus erythematosus, the NZB/W mouse. The roles of specific osteoclast receptors will be evaluated in several murine models of active bone remodeling including estrogen loss, parathyroid hormone infusion, and glucocorticoid administration. Our overall goal remains to better define the roles of innate immune receptors and their immunoregulatory effects so as to better understand their contribution to the autoimmune and normal immune responses.

Selected References

Chung, D.H., Humphrey, M.B., M.C. Nakamura, W.E. Seaman and M.R. Daws. CLM-1, a novel mouse myeloid receptor can inhibit in vitro osteoclast development . J Immunol 171(12):6541-8. 2003.

Humphrey, M.B., K. Ogasawara, W. Yao, S.C. Spusta, M.R. Daws, N.E. Lane, L. L., Lanier, and M.C. Nakamura. The Signaling Adapter Protein DAP12 Regulates Multinucleation During Osteoclast Development. JBMR 19(2):224-34, 2004.

Mócsai, A., Humphrey, M.B., Van Ziffle, J.A.G., Hu, Y. Burghardt, A., Spusta, S.C., Majumdar, S., Lanier, L.L., Lowell, C.A., and M.C. Nakamura. The Immunomodulatory Adapter Proteins DAP12 and FcRg Regulate Development of Functional Osteoclasts Through the Syk Tyrosine Kinase. PNAS Apr 20;101:6158-6163.

Website: http://medicine.ucsf.edu/rheum/faculty/nakamura.html

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