Elucidating Macrophage Heterogeneity in Systemic Sclerosis

Elucidating Macrophage Heterogeneity in Systemic Sclerosis

Principal Investigator: Patricia Pioli, PhD

Dr. Pioli received a B.S. in biology from George Washington University in 1993 and a Ph.D. in biochemistry from Dartmouth Medical School in 2001. She performed post-doctoral research with Dr. Paul Guyre at Dartmouth from 2001-2004, studying the mechanisms by which cortisol influences macrophage activation and immune function. She was appointed Research Assistant Professor of Physiology from 2004-2010. In July 2010, Dr. Pioli joined the faculty of Dartmouth Medical School as Assistant Professor in the Department of Obstetrics and Gynecology and Microbiology and Immunology.

Project Description

Systemic sclerosis (SSc) is a systemic autoimmune disease that results in widespread fibrosis of the skin and internal organs, vascular dropout and autoantibody formation. SSc has the highest case fatality rate of any systemic autoimmune disease and there remains an unmet need for FDA approved therapies. The scientific premise of this project is that SSc results from aberrant immune responses triggered by environmental triggers in the context of a predisposing genetic background. In this regard, multi-tissue bioinformatics analyses have indicated macrophages (MØs) are a driver of SSc in multiple end target organs. Activated MØs in SSc produce factors such as IL-6 and TGF-beta that drive disease, and co-culture studies have shown SSc-derived MØs can activate SSc dermal fibroblasts. These results suggest MØs are key drivers of pathogenesis and a common feature across organs in SSc patients. Targeting them directly is likely to reduce or ameliorate fibrosis in patients. Our overall hypothesis is that targeting activated MØs will provide a novel and effective approach to treat SSc. The studies will provide the basis for development of new hypotheses about the pathogenesis of SSc and related fibrotic conditions, leading to the identification of potential targets and therapies to treat patients based on underlying molecular defects.