The molecular and cellular pathways involved in tobacco smoke induced chronic obstructive pulmonary disease (COPD) pathogenesis are poorly understood. Autophagy is an intrinsic cellular program for the vesicular proteolytic turnover of proteins and dysfunctional organelles. Autophagy has been described in plants and yeast system for decades;however, in the last 5 years, we have witnessed the explosion of this field in mammalian systems. Generally, the process of autophagy involves rearrangement of intracellular membranes to sequester a specifically selected """"""""cargo"""""""" (including damaged or degraded proteins or organelles) within de novo formed membrane vesicles, or autophagosomes. As the process progresses, autophagosomes are transported along cytoskeletal structures by molecular motors such as dyneins and kinesins. Eventually, late autophagosomes fuse with lysosomes where the content is degraded and recycled to become an endogenous source of energy and nutrients. Autophagy was originally identified as a process that occurs during differentiation and development related to protein turnover. Recent studies have identified autophagy as a response to stress and starvation. Autophagy is now implicated in aging, immunity, cell death and in the progression of cancer and degenerative diseases. However, currently little is known on the role of autophagy in lung diseases. We have obtained intriguing preliminary data that both human COPD and preclinical in vivo models of COPD exhibit marked cellular autophagy. Based on these observations we propose the following hypothesis: Hypothesis: We hypothesize that autophagy plays a critical role in the pathogenesis of COPD and is associated with distinct clinical phenotypes in COPD. We further hypothesize that autophagy plays a critical determinant in airway disease and emphysema in COPD. To test this hypothesis, we will address the following Specific Aims:
Aim 1. To determine whether autophagy is a determinant of airways disease and emphysema in COPD.
Aim 2. To determine gene expression profiling in LCM derived cells from airways and emphysema, and to correlate with clinical phenotype including FEV1, QoL, and CT morphometry based airways disease or emphysema.

Public Health Relevance

Our preliminary data strongly suggest that autophagy is a major cellular and tissue response to tobacco smoke exposure in vivo and in human COPD. The autophagic responses may contribute to the pathogenesis of tobacco smoke induced COPD. We will examine whether autophagic responses associate with distinct clinical phenotype in COPD, namely airways and emphysema disease in COPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Research Grants (R03)
Project #
5R03HL097005-02
Application #
7837610
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Program Officer
Punturieri, Antonello
Project Start
2009-05-01
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$89,000
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Haspel, Jeffrey A; Choi, Augustine M K (2011) Autophagy: a core cellular process with emerging links to pulmonary disease. Am J Respir Crit Care Med 184:1237-46
Nakahira, Kiichi; Haspel, Jeffrey Adam; Rathinam, Vijay A K et al. (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222-30