Telomere integrity is essential for cell and organ function. In the presence of short telomeres, cells activate a DNA damage response that signals apoptosis and senescence. Clinically, these cellular programs manifest as progressive, degenerative organ failure. Because short telomeres accumulate with aging and impair tissue repair even when telomerase is wildtype, they have been implicated in mediating age-related disease. However, the consequences of telomere shortening in the lung are not fully understood. Aside from cigarette smoke exposure, age is the biggest risk factor for the development of emphysema. Emphysema incidence increases steadily with age and accounts for the fourth most common cause of mortality in the United States. The genetic mechanisms that lead to the age-related increase in emphysema are however not fully known. This proposal examines the role of short telomeres in emphysema susceptibility and pathogenesis in a relevant and genetically defined model, the telomerase knockout mouse. We hypothesize that short telomeres cooperate with cigarette smoke-related DNA damage to induce molecular defects that provoke the emphysema phenotype. Understanding the role of short telomeres in emphysema pathogenesis is particularly significant given recent observations that, in cigarette smokers, short telomeres are associated with the emphysema phenotype. The proposed studies therefore have the potential to advance knowledge about the genetic factors associated with aging that mediate the emphysema phenotype.

Public Health Relevance

This project examines the role of short telomeres in the pathogenesis of chronic obstructive pulmonary disease and the mechanism by which telomere shortening may be a susceptibility factor in emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL104345-02
Application #
8259422
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (03))
Program Officer
Postow, Lisa
Project Start
2011-04-15
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$246,000
Indirect Cost
$96,000
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Armanios, Mary (2013) Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest 123:996-1002
Alder, Jonathan K; Guo, Nini; Kembou, Frant et al. (2011) Telomere length is a determinant of emphysema susceptibility. Am J Respir Crit Care Med 184:904-12