Diverse injury to the lung from endogenous as well as environmental factors or agents may result in a stereotypic response leading to fibrosis and end stage lung disease with a potential fatal outcome. The long term objectives of this project are to determine the mechanisms underlying the genesis of the myofibroblast in lung injury and fibrosis, and to characterize the functional phenotype and roles of these cells in pulmonary fibrosis. The myofibroblast is a key source of mediators and extracellular matrix whose expression in fibrotic lesions is markedly stimulated. Fibrotic foci composed of myofibroblasts and other fibroblast phenotypes are diagnostic of idiopathic pulmonary fibrosis, a virtually fatal disease with no effective therapy. Hence understanding how these cells arise and the mechanisms regulating their survival may provide novel insight into the pathogenesis of pulmonary fibrosis. A number of mediators are known to induce myofibroblast differentiation in fibroblasts, however recent studies suggest additional derivation from epithelial cells through a process termed epithelial-mesenchymal transition (EMT). The central hypothesis of the proposal is that mediator induced genesis of the myofibroblast is dependent on regulation by transcription factors and their cognate elements in the alpha-smooth muscle actin ((-SMA) promoter, and that expression of (-SMA has consequences on elaboration of other key elements of the myofibroblast phenotype and concomitant loss of epithelial phenotype in EMT. To test this hypothesis, four specific aims are proposed. First, transcriptional regulation of myofibroblast differentiation will be analyzed from the standpoint of (-SMA gene expression. Second, epigenetic mechanisms involved in regulation of this differentiation will be investigated. Third, the functional role of (-SMA gene expression will be analyzed with respect to its effects on key signaling pathways, gene expression, and cell survival/apoptosis. The role of (-SMA in inducing the cellular phenotypic features of the myofibroblast will be identified by examining the effects of specific inhibitors of its expression and ectopic or induced expression in cells not usually known to express this actin isoform. Finally, the specific impact of induced (-SMA expression on EMT will be examined by analysis of the effects on cellular signaling and expression of epithelial marker genes. The proposed work should reveal novel insights to understanding processes associated with the multitude of diseases known to cause fibrosis. PROJECT NARRATIVE. The proposed studies attempt to uncover key biological processes that are important in the emergence of an activated fibroblast phenotype in fibrotic diseases of the lung, such as idiopathic pulmonary fibrosis and lung disease associated with autoimmune diseases such as rheumatoid arthritis. Thus the project is directly relevant to improving current understanding of these diseases, many of which such as idiopathic pulmonary fibrosis, have no current effective treatment and often result in chronic lung disease with a fatal outcome. Such fibrosis or scarring may also affect lung diseases with increasing prevalence, such as asthma. Improvement in understanding these processes will provide much needed insight into potentially novel treatments as well as approaches for management of patients with these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052285-18
Application #
8236954
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
1994-09-30
Project End
2013-09-30
Budget Start
2012-04-01
Budget End
2013-09-30
Support Year
18
Fiscal Year
2012
Total Cost
$369,247
Indirect Cost
$121,747
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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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
Hinz, Boris; Phan, Sem H; Thannickal, Victor J et al. (2012) Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 180:1340-55
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

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