The broad long term objective is to elucidate the role of telomerase induction in pathogenesis of chronic fibrotic lung diseases, such as interstitial lung diseases, chronic obstructive pulmonary disease (COPD) and asthma. Induction of telomerase has been observed in animal models of lung injury and fibrosis, and recent evidence points to a potential role for telomerase in certain types of pulmonary fibrosis in humans related to reduced telomere length. But the precise role of telomerase, normally not expressed or expressed at low levels in adult somatic cells, remains unclear with respect to disease pathogenesis. There is also mounting evidence that telomerase may have additional functional significance beyond the mere maintenance of telomere length, including regulation of cell differentiation, gene expression and cell survival/apoptosis. The origin of the telomerase expressing fibroblast induced in animal models of pulmonary fibrosis is unclear and the mechanism underlying its genesis remains a mystery along with the tissue compartmentalization or localization of this induction. The central hypothesis of this project is that induction of telomerase expression in lung injury and fibrosis in fibroblasts promotes their survival with increased resistance to apoptosis and thus promotes fibrosis. Additionally it is hypothesized that a potential source of this telomerase expressing fibroblast is the bone marrow from where it is recruited by signals from the injured lung. Three major specific aims are proposed to test this hypothesis: 1) to identify and characterize the phenotype of the bone marrow-cells with induced telomerase expression in lung injury and fibrosis and determine the tissue compartmentalization of this induction, 2) to determine the mechanism of telomerase induction and genesis by analysis of the molecular regulation of telomerase gene expression, and 3) to analyze the role of this induced telomerase expression in pulmonary fibrosis by examination of its effects on cell survival, apoptosis, gene expression and telomere length maintenance. This will be combined with array studies to screen and identify putative telomerase-dependent target genes and transcription factors, some of which may be of import in regulating telomerase expression itself. Understanding the role and origin of the telomerase expressing cells should provide additional novel potential targets for therapy of fibrotic diseases that are progressive and often have a fatal outcome.
This research project will analyze the role of an enzyme complex called telomerase in chronic fibrotic lung diseases, such as in various interstitial lung diseases, including idiopathic pulmonary fibrosis. This enzyme is responsible for maintaining the length of telomeres, repeated pieces of DNA at the ends of chromosomes, but it is unknown why this enzyme is expressed at high levels in diseased lungs. This project will attempt to clarify the importance of this enzyme in the development of fibrotic lung disease and thus provide new insights into many of these diseases that currently lack an effective cure or therapy. It is hoped that attainment of the study's objectives will provide new ideas for effective treatment and management of these diseases.
|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|
|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|
|Hu, Biao; Gharaee-Kermani, Mehrnaz; Wu, Zhe et al. (2011) Essential role of MeCP2 in the regulation of myofibroblast differentiation during pulmonary fibrosis. Am J Pathol 178:1500-8|
|Liu, Tianju; Baek, Hyun Ah; Yu, Hongfeng et al. (2011) FIZZ2/RELM-* induction and role in pulmonary fibrosis. J Immunol 187:450-61|
|Hu, Biao; Wu, Yue Ming; Wu, Zhe et al. (2010) Nkx2.5/Csx represses myofibroblast differentiation. Am J Respir Cell Mol Biol 42:218-26|
|Hashimoto, Naozumi; Phan, Sem H; Imaizumi, Kazuyoshi et al. (2010) Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 43:161-72|
|Hu, Biao; Gharaee-Kermani, Mehrnaz; Wu, Zhe et al. (2010) Epigenetic regulation of myofibroblast differentiation by DNA methylation. Am J Pathol 177:21-8|
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