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.
|Liu, Tianju; Yu, Hongfeng; Ullenbruch, Matthew et al. (2014) The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis. PLoS One 9:e88362|
|Bodempudi, Vidya; Hergert, Polla; Smith, Karen et al. (2014) miR-210 promotes IPF fibroblast proliferation in response to hypoxia. Am J Physiol Lung Cell Mol Physiol 307:L283-94|
|Parker, Matthew W; Rossi, Daniel; Peterson, Mark et al. (2014) Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest 124:1622-35|
|Xia, Hong; Bodempudi, Vidya; Benyumov, Alexey et al. (2014) Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis. Am J Pathol 184:1369-83|
|Liu, Tianju; Ullenbruch, Matthew; Young Choi, Yoon et al. (2013) Telomerase and telomere length in pulmonary fibrosis. Am J Respir Cell Mol Biol 49:260-8|
|Nho, Richard Seonghun; Peterson, Mark; Hergert, Polla et al. (2013) FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas. PLoS One 8:e61017|
|Nakashima, Taku; Liu, Tianju; Yu, Hongfeng et al. (2013) Lung bone marrow-derived hematopoietic progenitor cells enhance pulmonary fibrosis. Am J Respir Crit Care Med 188:976-84|
|Hu, Biao; Wu, Zhe; Hergert, Polla et al. (2013) Regulation of myofibroblast differentiation by poly(ADP-ribose) polymerase 1. Am J Pathol 182:71-83|
|Hu, Biao; Phan, Sem H (2013) Myofibroblasts. Curr Opin Rheumatol 25:71-7|
|Hu, Biao; Wu, Zhe; Nakashima, Taku et al. (2012) Mesenchymal-specific deletion of C/EBPýý suppresses pulmonary fibrosis. Am J Pathol 180:2257-67|
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