Emphysema is a leading cause of disability and mortality in the United States and worldwide. Aside from cigarette smoke, age is the biggest risk factor for emphysema development. Emphysema has been considered by some as an age-related disease because the alveolar destruction that is its hallmark occurs in the normal aging lung. Telomere dysfunction is one of the best-characterized mechanisms of cellular aging. Our group has recently shown that telomere dysfunction is a determinant of emphysema susceptibility in mice as well as in some human families. This application builds on these findings to probe the mechanisms underlying telomere-mediated emphysema. Our focus is primarily on understanding how epithelial damage and cellular senescence contribute to emphysema, with age and in response to cigarette smoke.
The specific aims build on compelling data showing that telomere dysfunction in epithelial cells limits repair after injury, ad test whether telomere length is a relevant determinant of stem cell function in alveolar progenitor cells. Our proposed studies aim to advance paradigms of emphysema biology in the context of aging mechanisms with the goal of identifying new understanding of disease mechanisms and novel targets for treatment.
Emphysema is a major cause of disability, and it is the third leading cause of death in the United States. There are currently no effective treatments that slow its progressive course. Age is the biggest risk factor for emphysema;and this project aims to define the role of telomeres, a well-established mechanism of cellular aging, in emphysema biology with the goal of defining new paradigms for approaching its treatment.
|Stanley, Susan E; Armanios, Mary (2015) The short and long telomere syndromes: paired paradigms for molecular medicine. Curr Opin Genet Dev 33:1-9|
|Stanley, Susan E; Chen, Julian J L; Podlevsky, Joshua D et al. (2015) Telomerase mutations in smokers with severe emphysema. J Clin Invest 125:563-70|
|Alder, Jonathan K; Barkauskas, Christina E; Limjunyawong, Nathachit et al. (2015) Telomere dysfunction causes alveolar stem cell failure. Proc Natl Acad Sci U S A 112:5099-104|