Cigarette smoking is the greatest known single risk factor for the development of lung disease, being a dominant risk for the development of both emphysema and idiopathic pulmonary fibrosis. While pulmonary fibrosis and emphysema can co-exist in the same individual, our recent report indicates that subclinical idiopathic pulmonary fibrosis (IPF) is inversely associated with total lung capacity and emphysema in smokers. Along with the fact that most former smokers with IPF do not have radiographic evidence of emphysema, suggests that these patterns of disease are likely to be due to distinct consequences of smoking reflecting unique individual susceptibilities, and its associated differential pathogenetic pathway(s). We have assembled a team of investigators who have worked efficiently and synergistically to better understand the mechanism(s) by which cigarette smoke can induce either fibrotic or emphysematous, or both phenotype. We have integrated the expertise of investigators from COPD and IPF community, both basic and translational, to come together to tackle this important challenge. The impact of reaching this major goal will be significant in the pulmonary community as we hope to unravel new molecular targets and/or treatment(s) for COPD and IPF. We will attempt to reach our goals by the addressing the following projects and cores: Projects: 1) Homeostatic Role of Autophagy in Lung Emphysema and Fibrosis 2) Genetic Modifiers of TGF-Beta1 and Cigarette Smoke in Fibrosis and Emphysema 3) Genetics and Epigenetics of COPD and IPF 4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core

Public Health Relevance

The pathogenesis of COPD and IPF is poorly understood. In this program project we have integrated the expertise of investigators from COPD and IPF community, both basic and translational, to come together to better understand the pathogenesis of these chronic lung diseases, and hopefully identify new molecular targets in the treatment of these dreadful diseases in the future. (End of Abstract) Project 1 - Homeostatic role of autophagy in cigarette smoke-induced lung disease (Choi, Augustine M.K.) Resume and Summary of Discussion: This is a focused and comprehensive project investing a new potential pathogenesis pathway in two important pulmonary diseases. The investigator has excellent preliminary data illustrating the potential importance of the new mechanism and a complete, well designed experimental plan that anticipates many potential pitfalls and alternate approaches. The potential relevance of the pathway to be an important new target for disease modification is high and the likelihood of the studies being completed based on track record are also high. (End of Reviewers'Comments) (Description as provided by applicant): Cigarette smoke represents a common risk factor for chronic obstructive lung disease (COPD) and idiopathic pulmonary fibrosis (IPF), but it is not known why the same perturbation of homeostasis can lead to distinct disease phenotypes. While commonalities are shared by these two chronic lung diseases, it is differences between them that will best inform us about how defects in homeostatic mechanisms can lead to disease. We have observed strikingly divergent levels of autophagy in lung tissue from patients with COPD and IPF. Lungs from patients with COPD have increased morphological and biochemical indicators of autophagy, whereas lungs from patients with IPF exhibit low levels of these indicators, in many cases below control levels. Our experimental data indicate that in pre-clinical models of each disease, the response to manipulation of autophagy also diverges: Mice deficient in autophagy protein LC3B (leading to impaired autophagy) are resistant to cigarette smoke induced emphysema, whereas mice treated with rapamycin (an inducer of autophagy) are protected from bleomycin-induced flbrosis. Moreover, we have discovered in our in vitro studies that transforming growth factor-pi (TGF-pi) is capable of inhibiting autophagy via a mechanism that involves the mammalian target of rapamycin (mTOR) pathway. Our preliminary data lead us to hypothesize that autophagy is one of the central mechanisms determining progression towards emphysematous and/or fibrotic lung disease. We further hypothesize that the level of autophagy in the lung is regulated by TGF- TGF-pi. To test these hypotheses, we will address the following specific aims: 1) Determine the effect of TGF-pi on cigarette smoke induced autophagy. 2) Determine whether autophagy mediates emphysematous and/or fibrotic responses via mTOR independent or dependent pathway. 3) Determine the role of mitochondria derived reactive oxygen species (ROS) and mitophagy in the development of emphysema or pulmonary fibrosis. PUBLIC HEALTH RELEVANCE: Chronic obstructive lung disease and idiopathic pulmonary flbrosis represent two disabling chronic lung diseases that lack effective therapies. While a past history of smoking predisposes to both conditions, we do not understand the individual factors determining the development of disease. We have discovered that the level of autophagy is highly divergent in both diseases, and a better understanding of the impact and regulation of autophagy in these diseases will offer new avenues for the development of therapies. (End of Abstract)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL114501-01A1
Application #
8476322
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Punturieri, Antonello
Project Start
2013-09-06
Project End
2018-06-30
Budget Start
2013-09-06
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$2,345,576
Indirect Cost
$279,068
Name
Weill Medical College of Cornell University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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