Pathogenesis of progressive fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), remain poorly understood with many having no effective therapies. A key element in IPF is the presence of activated fibroblast phenotypes engaged in crosstalk with injured alveolar epithelial cells. Recently a key transcription factor, CCAAT enhancer binding protein p (C/EBPP) and its major isoforms, liver-enriched activator protein (LAP) and liver-enriched inhibitory protein (LIP), are found to be involved in regulation of myofibroblast differentiation, and critical for the development of pulmonary fibrosis in an animal model. However the regulatory mechanisms responsible for generation of the two isoforms, and their regulation of myofibroblast differentiation and pulmonary fibrosis remain to be elucidated. Two possible mechanisms for regulating LAP:LIP ratio have been proposed based on the control of different translation start sites by the translational initiation factor, elF4E and the CUG binding protein-1 (CUGBP-1), respectively. An additional mechanism is the use of an alternate transcriptional start site to generate the LIP isoform. While C/EBPp is known to regulate myofibroblast differentiation in vitro, additional mechanisms in vivo may be involved since this transcription factor is known to regulate other genes of potential relevance to fibrosis, including type I collagen, arginase I and elastin. Based on these previous findings, the central hypothesis of this project is that C/EBPp via its two key isoforms critically regulates myofibroblast differentiation and other target genes to promote and propagate pulmonary fibrosis. In common with the othre two projects, the focus is on elucidating the various fibroblast phenotypes that are central to IPF and the mechanisms of their genesis.
The Specific Aims to test this hypothesis are to, 1) determine the mechanisms regulating C/EBPbeta isoform expression, 2) evaluate post-translational modification of C/EBPP and its significance in regulation of target gene expression, 3) investigate how C/EBPP regulates pulmonary fibrosis in vivo by use of C/EBPp knockout mice in bone marrow chimera studies, and 4) identify key C/EBPp target genes in vivo and in isolated lung fibroblasts. The upstream signaling and translational control studies have common elements with Projects 1 and 2, respectively, which should synergize the various projects.
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