SHIVA SHAHRARA RESEARCH

Shiva Shahrara, PhD

In the United States, 2.5 million people have rheumatoid arthritis (RA). RA is a chronic inflammatory autoimmune disorder that starts in the young to middle adult years and may lead to complete joint destruction. There is no cure for RA at present and a substantial percentage of patients do not respond to current therapy, therefore novel therapeutic approaches are urgently needed. To address this important issue, my laboratory focuses on identifying new targets and/or biomarkers for RA disease severity and response to effective therapy. To identify these novel targets or biomarkers for RA severity, we performed microarray studies in order to determine differentially regulated genes in macrophages obtained from synovial fluid of RA patients with active disease compared to normal macrophages and have found a number of important targets. We next examine the mechanism by which these factors mediate RA pathology initially utilizing RA peripheral blood, synovial tissue and synovial fluid and we subsequently determine whether blockade of this these factors could ameliorate the experimental arthritis model through the same underlying pathways identified in RA specimens.

A number of factors identified in our microarray analysis were shown to be important for monocyte extravasation. Monocyte migration plays a key role in the pathogenesis of RA since the number of monocyte derived macrophages is higher in RA compared to normal joints and is well correlated with radiological damage, joint pain and inflammation. Macrophages play a central role in RA pathogenesis by producing proinflammatory cytokines and chemokines, matrix metalloproteinases(MMPs), proangiogenic factors and differentiating to osteoclasts. Hence, factors modulating monocyte ingression can mediate inflammation and bone erosion. Therefore, one of the main objectives of our laboratory is to determine the molecular mechanism(s) responsible for enhanced recruitment of monocytes into the RA synovial joint space.

Another research interest in our laboratory is to inhibit angiogenesis in the early disease onset since angiogenesis is an early and a critical event in the pathogenesis of RA that promotes ingress of leukocytes and pannus formation thereby inhibition of neovascularization may block chronic inflammation.

A more recent interest that is being pursued is the identification of novel factors in RA synovial fluid and/or tissue that may be essential or are capable of synergizing with other known proinflammatory cytokines in inducing RA bone and cartilage erosion.

In short we hope that by taking a bench to bed side approach we will be successful in performing translational studies that would allow us to A. determine novel targets that inhibit neovascularization, monocyte recruitment and bone erosion in the RA joint and B. identify biomarkers that reflect RA disease severity and/or response to effective treatment.