Increased numbers of fibroblasts are a key feature of pulmonary fibrosis, and their coalescence in densely populated cell formations, termed fibroblastic foci, is a diagnostic histopathological feature of idiopathic pulmonary fibrosis (IPF). Increased proliferation is a likely mechanism for this increase in fibroblasts whose phenotype is distinct from cells isolated from normal lung. Interestingly a new fibroblast phenotype is found to emerge in animal models of lung injury and fibrosis characterized by the expression of telomerase activity. While telomerase activity is associated with increased proliferative capacity and life span in certain cells during early development and many tumor cells, its significance in the pathogenesis of pulmonary fibrosis is unknown. In this project it is hypothesized that emergence de novo of a telomerase-expressing fibroblast phenotype is induced by certain factors resulting in increased cell proliferation and/or survival. This would increase the pool size of proliferative cells serving as an intermediate differentiated population that can terminally differentiate to the myofibroblast phenotype.
Four specific aims are proposed to test this hypothesis. First, the mechanism of telomerase induction will be studied in lung fibroblasts. The telomerase gene and its 5'-flanking sequences will be cloned for analysis of transcriptional regulation. Second, the relationship between the telomerase expressing and myofibroblast phenotypes will be examined by analyzing the relationship between telomerase and (-smooth muscle actin gene expression, and whether the transcriptional regulatory mechanisms for both genes are somehow related in a functionally meaningful way in terms of cellular differentiation. Third, the functional significance of telomerase expression will be analyzed by comparing telomere length with telomerase expression in vivo and in vitro, and whether telomerase expression endow cells with differential characteristics with respect to response to growth factors and/or apoptotic signals. Finally, the role of telomerase in pulmonary fibrosis will be examined in vivo in the bleomycin model by use of telomerase (either telomerase reverse transcriptase or telomerase RNA component) knockout mice as well as specific telomerase inhibitors. By using these combined approaches, new insights into the potential role and significance of this telomerase expressing phenotype will be uncovered, which may prove to be useful for devising future novel therapeutic approaches.
| Hu, Biao; Liu, Jianhua; Wu, Zhe et al. (2015) Reemergence of hedgehog mediates epithelial-mesenchymal crosstalk in pulmonary fibrosis. Am J Respir Cell Mol Biol 52:418-28 |
| 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 |
| Ding, Lin; Dolgachev, Vladilsav; Wu, Zhuang et al. (2013) Essential role of stem cell factor-c-Kit signalling pathway in bleomycin-induced pulmonary fibrosis. J Pathol 230:205-14 |
| 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 |
| 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; Nakashima, Taku et al. (2012) Mesenchymal-specific deletion of C/EBPýý suppresses pulmonary fibrosis. Am J Pathol 180:2257-67 |
| Phan, Sem H (2012) Genesis of the myofibroblast in lung injury and fibrosis. Proc Am Thorac Soc 9:148-52 |
| 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 |
Showing the most recent 10 out of 28 publications
