Deciphering the Regulation of TGF-b3 in Driving Myofibroblast Differentiation in Systemic Sclerosis

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

SUMMARY/ABSTRACT This application is for a K01 Mentored Research Scientist Development Award entitled “Deciphering the Regulation of TGF-3 in Driving Myofibroblast Differentiation in Systemic Sclerosis”, submitted by Dr. Mengqi Huang, a Research Instructor within the Division of Rheumatology and Clinical Immunology at the University of Pittsburgh. The short-term goals detailed in this submission are designed to help the applicant achieve her long-term objective of becoming an independent scientist and leader in the field of SSc research. These short- term goals include (1) advancing knowledge of computational biology and disease rodent model (2) development of technical and analytic tools to effectively identify and validate epigenetic targets, and (3) development of leadership skills to obtain academic independence. This work will be completed in the Division of Rheumatology and Clinical Immunology at the University of Pittsburgh, a rich research environment with a strong commitment to and proven track record of fostering the development of medical research scientists. The central objective of this research proposal is to investigate the epigenetic regulatory networks driving increased expression of TGF- 3 in SSc skin myofibroblasts, which are the key effector cell in fibrosis and no treatments currently exist to target these cells. Increased transcription of TGF-3 has been shown a significant correlation with skin fibrosis severity of SSc patients, and a newly published study showed that selectively inhibition of TGF-3 can sufficiently reduce lung fibrosis in a SSc-relevant mice model. However, the regulation of elevated TGF-3 expression in the pathogenic myofibroblasts remains unknown. My preliminary data implicates SSc myofibroblasts as the primary source of TGF-3 in skin, and the FRA-2/FOSL2 transcription factors (TF) as putative positive regulators of TGF-3 transcription. The primary hypothesis is that TGF-3 regulated by FOSL2 (and/or other TF) reflects the underlying transcriptional landscape of myofibroblast differentiation and mediates SSc fibrosis. With this proposal, the applicant will expand on her prior work with the following specific aims: (1) Identify the DNA cis- regulatory element(s) of TGF-3 in SSc skin fibroblasts, (2) Investigate FRA-2/FOSL2 or other upstream regulator(s) of TGF-3 in SSc patients by integrating transcriptomic and epigenetic profiles of skin fibroblasts at the single cell level, and (3) Assess the importance of TGF-3 in driving fibrosis in relevant murine models of SSc. This proposal will determine the role of TGF3 and its regulator FRA-2/FOSL2 (or other TF) in mediating myofibroblast differentiation in vitro and organ fibrosis in vivo.