One of the manifestations of aging is the accumulation of damage at both cellular and organism levels. Genotoxic stress plays an important role in aging and age-related diseases such as emphysema, which is caused by a failure of lung maintenance and repair after sustained oxidative stress. Cigarette smoke represents a source of oxidants and is considered an environmental hazard that causes pulmonary emphysema. Premature senescence is believed to contribute to genotoxic stress-induced emphysema. The tumor suppressor protein p53 is a key regulator of premature senescence and is activated by the ataxia-telangiectasia mutated (ATM) protein kinase when the ATM inhibitor protein phosphatase 2A (PP2A) dissociates from ATM after genotoxic stress. The mechanism underlying PP2A-C removal from ATM upon genotoxic stress remains totally unexplored. In addition, the role that the ATM/p53 pathway plays in cigarette smoke-induced cellular senescence and the pathogenesis of emphysema remains largely unknown. Here, we plan to test the hypothesis that the lipid raft protein caveolin-1 mediates stress-induced premature senescence by promoting ATM-dependent activation of p53 through sequestration of the ATM inhibitor PP2A-C into caveolae. In addition, it is hypothesized that caveolin-1 plays a central role in oxidant-promoted emphysema in vivo through induction of cellular senescence. This hypothesis will be tested by pursuing three specific aims:
Specific Aim 1 : Investigate the role of caveolin-1 in PP2A-mediated regulation of ATM function after genotoxic stress.
Specific Aim 2 : Determine the functional consequences of loss of caveolin-1 expression on ATM-mediated p53 activation and premature senescence.
Specific Aim 3 : Define the role of caveolin-1 in genotoxic stress-induced pulmonary emphysema in vivo. These studies will provide novel insights into the signaling machinery that links genotoxic stress to cellular senescence and propose caveolin-1 as a novel therapeutic target for the treatment of age-related diseases such as emphysema.

Public Health Relevance

Oxidative stress, including cigarette smoke, promotes premature cellular senescence, which is believed to have an important role in the more complicated aging process, and contributes to age-related diseases like emphysema. The molecular mechanisms underlying cigarette smoke-induced emphysema are not fully understood. Our studies will test the hypothesis that the protein caveolin-1 is a novel regulator of stress-induced cellular senescence and emphysema, and propose caveolin-1 as an alternative therapeutic target for the treatment of age-related diseases such as emphysema.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030636-05
Application #
8507585
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$274,728
Indirect Cost
$90,381
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Peffer, Melanie E; Chandran, Uma R; Luthra, Soumya et al. (2014) Caveolin-1 regulates genomic action of the glucocorticoid receptor in neural stem cells. Mol Cell Biol 34:2611-23
Salem, Ahmed F; Al-Zoubi, Mazhar Salim; Whitaker-Menezes, Diana et al. (2013) Cigarette smoke metabolically promotes cancer, via autophagy and premature aging in the host stromal microenvironment. Cell Cycle 12:818-25
Volonte, Daniela; Liu, Zhongmin; Musille, Paul M et al. (2013) Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence. Mol Biol Cell 24:1852-62
Zou, Huafei; Stoppani, Elena; Volonte, Daniela et al. (2011) Caveolin-1, cellular senescence and age-related diseases. Mech Ageing Dev 132:533-42
Volonte, Daniela; Galbiati, Ferruccio (2011) Polymerase I and transcript release factor (PTRF)/cavin-1 is a novel regulator of stress-induced premature senescence. J Biol Chem 286:28657-61
Hezel, Michael; de Groat, William C; Galbiati, Ferruccio (2010) Caveolin-3 promotes nicotinic acetylcholine receptor clustering and regulates neuromuscular junction activity. Mol Biol Cell 21:302-10
Volonte, Daniela; Galbiati, Ferruccio (2009) Inhibition of thioredoxin reductase 1 by caveolin 1 promotes stress-induced premature senescence. EMBO Rep 10:1334-40
Volonte, Daniela; Galbiati, Ferruccio (2009) Caveolin-1, cellular senescence and pulmonary emphysema. Aging (Albany NY) 1:831-5