Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease without effective therapies. We have established with our reported observations and preliminary studies that heme oxygenase-1 (HO-1) and its enzymatic product, carbon monoxide (CO), provide protection against bleomycin-induced lung fibrosis. We have also shown that CO inhibits fibroblast expression of (-smooth muscle actin and matrix production in response to transforming growth factor-(1 (TGF-(1). These effects of CO do not depend upon previously described signaling pathways for CO. Instead, our preliminary studies indicate that CO relies for these effects upon the presence of inhibitor of differentiation-1 (Id1), a transcriptional regulator that is a member of the basic helix-loop-helix family of proteins. The regulation and function of Id1 in fibrosis is not known, although Id1 is highly responsive to TGF-(1 in multiple cell types. Our preliminary data indicate that mice lacking the gene for Id1 are highly susceptible to bleomycin-induced lung injury, and that fibroblasts lacking Id1 exhibit enhanced reactions to TGF-(1 stimulation. As the effects of CO and Id1 in fibrosis could not be explained by known mechanisms, we performed protein interaction screening studies to identify novel effector pathways. We have identified a new binding partner for Id1, known as dead ringer-like-1 (Dril1). Dril1 shares structural similarities with Id1 and was recently implicated in TGF-(1 signaling during embryogenesis. To date, little is known about the function of Dril1 in humans. Although it has not been implicated in fibrotic disease, we found that Dril1 is highly expressed in IPF lung and is regulated by TGF-(1 in human fibroblasts. Dril1 enhances activation of TGF-(1 target genes, whereas Id1 decreases expression of these same molecules. Our preliminary data indicates that Dril1 can physically interact with Smad3 in a TGF-(1-dependent fashion, and that Id1 inhibits DNA binding by Dril1, suggesting a potential mechanism for suppression of fibrosis by Id1. The goal of this proposal is to determine how Id1 and its interactor, Dril1, impact the progression of fibrosis. Our overall hypothesis is that CO relies upon Id1 for its anti-fibrotic effect. We further hypothesize that Id1 modulates the progression of fibrosis by inhibiting the transcriptional regulator, Dril1, and that this effect occurs in concert with the Smad signaling pathway. To test these hypotheses we will: 1) Determine whether Id1 mediates the effect of CO in a murine model of lung fibrosis. 2) Determine the mechanism by which Id1-binding partner Dril1 mediates fibroblast responses to TGF-(1. 3) Establish the relationship between Id1/Dril1 and the Smad family of signal transducers. Relevance of this research to public health - Fibrosis is a feature of many chronic diseases, and the unfortunate consequence of loosing normal organ tissue to scar formation is functional impairment or outright organ failure. Idiopathic pulmonary fibrosis (IPF) represents a particularly frustrating challenge for the clinician, because so little is known about the cause of the disease, and current therapies are ineffective or only marginally effective. There is therefore an urgent need for further research to elucidate the pathogenesis of idiopathic pulmonary fibrosis and to identify potential therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087122-05
Application #
8197318
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
2009-04-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$389,837
Indirect Cost
$167,087
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Zheng, Liang; Zhou, Zhihong; Lin, Ling et al. (2009) Carbon monoxide modulates alpha-smooth muscle actin and small proline rich-1a expression in fibrosis. Am J Respir Cell Mol Biol 41:85-92
Lin, Ling; Zhou, Zhihong; Zheng, Liang et al. (2008) Cross talk between Id1 and its interactive protein Dril1 mediate fibroblast responses to transforming growth factor-beta in pulmonary fibrosis. Am J Pathol 173:337-46