• Title Emeritus Professor
  • Education PhD: Boston University

Our laboratory contributed to the understanding of the mechanisms involved in the control of collagen gene expression associated with inflammation, atherosclerosis, tumors, and fibrotic diseases including systemic sclerosis.   Collagen, a  family of extracellular proteins, plays a critical role in remodeling after injury. Progressive deposition of excess extracellular matrix (ECM), occurs in a large group of diseases with no effective therapy  including cardiovascular disease, pulmonary fibrosis, diabetic nephropathy, systemic sclerosis, and liver cirrhosis. Fibrosis (excessive scarring) is a progressive deposition of excess collagen-rich extracellular matrix produced by activated myofibroblasts leading to impairment and finally failure of affected organs.  In normal healing following injury, fibroblasts differentiate into myofibroblasts. If progression to fibrosis occurs, these myofibroblasts do not undergo apoptosis but instead continue to proliferate and produce excess amounts of ECM. Isolated primary fibroblasts from fibrotic lesions maintain their activated myofibroblast phenotype containing abundant stress fibers with smooth muscle actin (SMA).  Myocardin related transcription factors (MRTF-A, MRTF-B), members of the myocardin family, link actin dynamics with gene transcription. Our data indicate that MRTF-A dramatically (100 fold) activates collagen transcription.  Fibroblasts with knockdown of MRTFA have different morphology and produce less collagen and SMA. We hypothesize that MRTFA plays a central role in activation and perpetuation of myofibroblast during the development of fibrotic disease.

Our laboratory has also examined both activation and repression of collagen transcription using molecular biology approaches.  We have demonstrated that collagen type I genes are methylated in the first exon in cancer cells and colon cancer. Collagen gene is silenced in certain tumors. A methylation sensitive DNA binding protein (RFX1) represses transcription by binding to the collagen gene transcription start site. This protein belongs to a family of proteins that can function as transcription activators or repressors. RFX1 interacts with a co-repressor complex containing histone deacetylase which could be involved with spreading of DNA methylation and silencing. A RFX5 complex containing three other proteins (RFXANK/B, RFXAP, CIITA) are essential activators of major histocompatibility complex class II (MHC II) proteins that respond to interferon-gamma during inflammation and activate cells to become antigen producing cells. Interferon activates RFX5/CIITA synthesis and nuclear localization in human fibroblasts and smooth muscle cells. RFX5 proteins form a complex at the RFX site at the collagen gene transcription start site and recruits CIITA to repress collagen transcription through a phosphorylation sensitive interaction with co-repressor complex. Thus, this family of proteins may be very important modulators of collagen expression during inflammation.

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