Antifibrotic effects of Syndecan-2 and CD148 in Rheumatoid Arthritis Interstitial Lung Disease

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Project Summary/Abstract: This K01 proposal describes a five-year research and training plan that will facilitate the transition of Dr. Konstantin Tsoyi to an independent academic researcher in the field of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Dr. Tsoyi has a strong background in molecular biology and pharmacology and has completed post-doctoral training in immunology and lung fibrosis. RA is a systemic inflammatory disorder affecting approximately 3 million people in the United States. ILD is the most common lung complication of RA and is associated with increased mortality. RA-ILD occurs in approximately 10% of patients with advanced RA, and another 30% with early disease, half of whom will progress. Little is known about the molecular mechanisms involved in the pathogenesis of RA- ILD. The current application endeavors to create a niche of basic and translational investigation to better understand the role of fibroblasts, in the pathophysiology of RA-ILD with the ultimate goal of developing therapeutic interventions. The candidate has previously demonstrated the antifibrotic properties of syndecan-2 (SDC2), a member of the heparan sulfate proteoglycan family, in an animal model of radiation-induced pulmonary fibrosis. The overarching aim of this proposal is to delineate the role of SDC2 in a model of RA-ILD using in vivo and in vitro approaches. The applicant hypothesizes that SDC2 deficiency increases susceptibility to experimental lung fibrosis in an established arthritis murine model. Furthermore, SDC2 exerts antifibrotic effects by activating CD148 (a membrane-bound protein tyrosine phosphatase) and reducing PI3K/Akt/Sp1 signaling and peptidylarginine deiminase-2 (PAD2) expression in lung fibroblasts. The significance of this research is that knowledge gained from this study will contribute to the development of future therapeutics for patients affected with RA-ILD. Dr. Tsoyi will receive mentorship from his scholarship oversight committee, composed of distinguished scientists with expertise related to key areas of this proposal, including lung fibrosis, RA and fibroblast biology. The training opportunities and resources at Brigham and Women’s Hospital (BWH) and Harvard Medical School (HMS) provide an ideal environment for the candidate’s career development. The Department of Medicine at BWH is committed to Dr. Tsoyi’s success and has assured 100% protected time to devote to the activities described in this proposal. The candidate’s mentors, Drs. Ivan Rosas and Michael Brenner, are NIH-funded investigators and leaders in the fields of interstitial lung disease and rheumatoid arthritis. This application outlines a detailed career development and training plan that includes the proposed mentored research, didactic coursework, self-directed readings, seminars, and presentations at scientific meetings. The expertise and knowledge gained from this K01 will enable Dr. Tsoyi to obtain R01 funding to launch an independent research career focused on the study of molecular mechanisms involved in the development of RA-ILD.