Ellen M Gravallese MD
|Institution||University of Massachusetts Medical School|
|Address||University of Massachusetts Medical School|
364 Plantation Street, LRB
Worcester MA 01605
|Institution||UMMS - School of Medicine|
|Department||Cell and Developmental Biology|
|Institution||UMMS - Graduate School of Biomedical Sciences|
Research in my laboratory is devoted to the study of the pathogenesis of rheumatoid arthritis (RA), with particular interest in the fundamental mechanisms of bone and cartilage destruction. Through studies of human tissues using pathologic and molecular techniques, murine models of disease and in-vitro assays, this research has contributed to the development of new clinical interventions. Research areas can be summarized into four major categories: 1) Identification of cell types and pathways that drive osteoclastogenesis. 2) Identification of the effects of synovial inflammation on inhibiting osteoblast function and bone formation, thus inhibiting bone repair. 3) Identification of the role of innate immune pathways, in particular the cytosolic DNA sensor and endosomal TLR pathways, in the regulation of specific manifestations of autoimmunity. 4) Role of microRNAs in the regulation of autoimmune diseases and bone.
Initial work in my laboratory identified the cells responsible for bone erosion in RA by demonstrating that osteoclasts are the essential cells in articular bone loss in RA. We further identified synovial fibroblasts and activated CD4+ T lymphocytes in RA synovium as sources of RANKL, a cytokine required for osteoclast differentiation and activation. The essential role of RANKL and of osteoclasts in bone erosion in RA was demonstrated in my laboratory through the generation of arthritis (by serum transfer) in RANKL-deficient mice. We have also demonstrated the impact of inflammation in the bone microenvironment on osteoblasts, showing that osteoblast maturation and function is compromised at sites of inflammation in bone, inhibiting bone repair. We showed that inhibitors of the Wnt signaling pathway, including DKK family members, contribute to the inhibition of osteoblast function and bone formation at sites of erosion. We have initiated a clinical trial in RA to assess the efficacy of intermittent PTH, an anabolic agent, in promoting the healing of articular erosions in RA.
Finally, in a new direction for my laboratory, we are working to understand the contribution of innate and adaptive immune mechanisms to the onset, progression, persistence and regulation of systemic autoimmune diseases, with particular attention to RA and systemic lupus erythematosus. The past decade has seen a paradigm shift in our understanding of the mechanisms underlying autoimmune and inflammatory diseases. We have come to realize that aberrant regulation of innate immune system components has a major impact on disease etiology. Our work has led to insights into specific pathways regulating distinct autoimmune manifestations, providing new targets for intervention in these diseases.
Several projects are open to rotating students, including projects in the area of innate immunity and DNase II deficient mice, effects of inflammation on bone in rheumatic diseases, and regulation of arthritis and bone destruction by microRNAs.
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