Emphysema causes an enormous health burden within the United States and worldwide. Smoking and advanced age are the biggest risk factors for its development, yet the genetic factors that contribute to emphysema susceptibility and its associated age-related onset are largely unknown. Telomeres are DNA and protein structures that protect the ends of chromosomes. Each time a cell divides, telomeres shorten and short telomeres activate a DNA damage response that triggers cell death or cell cycle arrest. Telomere lengths are heterogeneous in the population and shorten with age;but the link between telomeres and emphysema has not been explored in animal models. This proposal builds on exciting preliminary data we have generated that mice with short telomeres are more susceptible to cigarette smoke (CS) and develop emphysema. We have found that short telomeres limit the ability of lung epithelial cells to repair and recover after injury. This projet will use mice with dysfunctional telomeres as a model system for studying emphysema biology and explore mechanisms that underlie its pathogenesis. In the first aim, we will genetically remove a key downstream regulator of cell cycle arrest following DNA damage and test if this rescues telomere-induced CS susceptibility. In the second aim, we will generate a new model to probe the consequences of telomere dysfunction in individual cell types within the lung to define the cellular basis for the emphysema susceptibility. Finally, in the third aim, we will examine the secreted proteins that mediate telomere-induced lung restructuring;this is the subject of the independent portion of this research. The proposed studies have potential to identify key pathways that contribute to emphysema pathogenesis. When identified, these mediators could potentially be targeted to treat or prevent emphysema. I have chosen an outstanding environment and group of mentors to complete the final years of my training. During the training period, I anticipate that the environment and additional training plan I have formulated will prepare me to establish an independent group that can make significant advances in translational lung research.
Emphysema is an enormous health problem within the United States, causing more than 100,000 deaths each year. Currently, the treatment options are very limited. This proposal examines the mechanisms by which short telomere length predisposes to cigarette smoke-induced emphysema with the goal of identifying new therapeutic strategies.
|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|
|Alder, Jonathan K; Parry, Erin M; Yegnasubramanian, Srinivasan et al. (2013) Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. Hum Mutat 34:1481-5|