Tissue repair is characterized by the de novo but transient appearance of myofibroblasts, commonly identified by their expression of ?-smooth muscle actin (?-SMA). But their persistence is associated with chronic fibrosis that progressively leads to loss of function of the affected organ. Thus, elucidation of the mechanism of their derivation may provide insight into the pathogenesis of chronic progressive fibrotic diseases. Multiple mechanisms are implicated in genesis of the myofibroblast from diverse cellular precursors, including diverse signaling pathways, transcription and epigenetic factors. While poly(ADP-ribose) polymerase 1 (PARP-1) is initially discovered to be activated by, and is thus a sensor of DNA damage, it is now considered to play additional important roles in signal transduction and regulating gene expression via both transcriptional and epigenetic mechanisms. While this enzyme gets its name from its ability to catalyze poly(ADP-ribosyl)ation in post-translational modification of acceptor proteins, it can also regulate gene transcription independent of its catalytic activity. Its ability to modulate DNA methylation through interactions with DNA methyltransferases 1 (Dnmt1) would have implications on ?-SMA gene expression given the importance of this epigenetic regulation in myofibroblast differentiation. In vivo NAD+ depletion by activated PARP in lung injury is associated with fibrosis, and cardiac, renal and peritoneal fibrosis are diminished by PARP-1 deficiency, while epithelial-mesenchymal transition appears to be PARP-1 dependent. Given this body of evidence, the central hypothesis of this project is as follows. De novo genesis of the myofibroblast in tissue fibrosis is dependent on the pleiotropic role of PARP-1 in regulating signaling pathways, transcription and epigenetic factors affecting differentiation. Thus the aims are 1) to study the role of PARP-1 in pulmonary fibrosis using conditional knockout mice, 2) to determine the mechanism by which PARP-1 regulates transcription of the ?-SMA gene and associated signaling pathways, 3) to analyze PARP-1 regulation of DNA methylation of the ?-SMA gene, 4) to identify PARP-1 target genes involved in regulation of ?-SMA expression and confirm their impact on myofibroblast differentiation. Using this combination of molecular biological, biochemical and immunological tools, the proposed project will evaluate the specific roles of PARP-1 in these targeted areas that are known to promote myofibroblast differentiation in pulmonary fibrosis. If confirmed the availability of multiple PARP inhibitors should make PARP-1 a ready target for exploration as an anti-fibrotic therapy.

Public Health Relevance

Understanding how poly(ADP-ribose) polymerase I regulates myofibroblast differentiation would shed light on its role in chronic progressive fibrotic diseases such as in idiopathic pulmonary fibrosis, scleroderma, asthma, liver cirrhosis, etc. Many of these diseases have no effective therapy and gradual loss of vital organ function due to progressive replacement by fibrotic or scar tissue may result in a fatal outcome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL052285-19A1
Application #
8629396
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
1994-09-30
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
19
Fiscal Year
2014
Total Cost
$388,750
Indirect Cost
$138,750
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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