TGF-beta receptor/Endoglin signaling and the origin of scleroderma fibroblast

Boston University Medical Campus, Boston MA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Scleroderma (Systemic Sclerosis, SSc) is a devastating multiorgan disease with a prevalence of approximately 250 cases per million people in the US. Despite significant therapeutic advances, pulmonary and cardiac complications are associated with high mortality, and no effective therapy is currently available. Prominent skin and organ fibrosis is a hallmark feature of SSc and is accompanied by fibroproliferative vasculopathy and immune dysfunction. Extensive characterization of fibroblasts isolated from SSc lesions revealed numerous phenotypic alterations, consistent with persistent activation of the autocrine TGF?ignaling pathway. However, a gap in our understanding exists in how these phenotypically altered fibroblasts emerge and which factors are responsible for their expansion and/or activation. Our studies focusing on the profibrotic mechanisms in SSc revealed an important role for the Endoglin (ENG) receptor complex in activating SSc fibroblasts. We showed that ENG is part of a multiprotein complex that also contains TGF?eceptors ALK5 and ALK1, as well as arrestin ?(ARRB1) and S1P1 receptor (S1PR1). The proposed studies will test the hypothesis that CCN2 and PDGF-A/PDGFR?ediated activation and expansion of peri-vascular stromal cells plays a central role in SSc fibrosis. Specifically, we hypothesize that signaling through the ENG receptor complex and its downstream target gene CCN2 play a key role in this process. To test our hypotheses we propose three Specific Aims. In Aim 1 we will investigate the role of the Endoglin receptor complex in the development of dermal fibrosis. In Aim 2 we will determine the functional contribution of pericyte-like cells to SSc dermal fibrosis. In Aim 3 we will investigate the role of CCN2 and PDGF-A in the expansion and fibrogenic differentiation of peri-vascular cells during the development of dermal fibrosis. This proposal wil provide important information on the pathogenic role of ENG, CCN2 and PDGFR?s key driver signaling pathways involved in the development of fibrosis in SSc. Furthermore, it will provide preclinical information about the effectiveness of targeting these signaling pathways for the treatment of SSc.