This proposal is the A1 submission for competitive renewal of R01 HL65352, """"""""Alveolar Epithelial Cells: Development and Repair."""""""" Our previous studies showed that the sub-population of alveolar epithelial type 2 cells (AEC2) that proliferate following oxidative lung injury exhibit a significant increase in telomerase activity, which recapitulates the elevated activity observed in fetal and neonatal AEC2. We also showed that those same lung cells that exhibit increased telomerase expression following injury are significantly more resistant to oxidative damage than a normoxia-exposed population. Our more recent studies show that lung cells from a telomerase null model, the terc-/- mouse, are targets for such damage and exhibit both chronic levels of oxidative stress and evidence of imperfect repair. These observations are a phenocopy of the debilitation leading to disease in aged lung. Taken together, our published findings and the preliminary data presented in this proposal show that activation of telomerase and maintenance of telomere integrity support both lung cell resistance to damage and normal ability to repair, while aging, telomerase knockdown and telomere shortening compromise both these activities. These findings indicate that telomerase activity and properly maintained telomeres correlate with both a lung cell survivor phenotype and a youthful whole lung phenotype. The chronically stressed molecular profile of aged and terc-/- cells implies that they are much less capable of normal tissue maintenance and injury repair than youthful and telomerase competent cells. We speculate that alteration of telomere length and stress signaling in terc-/- and aged lung stem/progenitor cells may lay the foundation for the variety of lung diseases and conditions for which telomerase mutation and aging are both risk factors. Aging and telomerase dysfunction alter stem/progenitor cell integrity and function in distal lung epithelium. To test this hypothesis, three specific aims are proposed: 1) To determine the mechanism that underlies the chronic stress phenotype and hypersensitivity to injury of aged and terc-/- AEC2, 2) To determine how aging, telomerase knock down and/or changes in telomere length compromise bronchioalveolar stem cell (BASC) progenitor function in vitro and 3) To determine how aging and telomerase dysfunction alter the ability of stem/progenitor cells to repair distal lung epithelium in a novel, targeted AEC2 depletion model.

Public Health Relevance

Aging and telomerase/telomere dysfunction have a significant impact on lung tissue integrity. In this proposal, we will determine the impact of aging, telomerase knockdown and acute telomere shortening on the lung stem/progenitor cell functions of normal tissue maintenance and injury repair. These studies will generate both basic, mechanistic insight into the role of telomerase in lung stem/progenitor cell function and provide possible targets for future therapies for age-related lung debilitation and disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Blaisdell, Carol J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital of Los Angeles
Los Angeles
United States
Zip Code
Garcia, Orquidea; Hiatt, Michael J; Lundin, Amber et al. (2016) Targeted Type 2 Alveolar Cell Depletion. A Dynamic Functional Model for Lung Injury Repair. Am J Respir Cell Mol Biol 54:319-30
Lundin, Amber; Driscoll, Barbara (2013) Lung cancer stem cells: progress and prospects. Cancer Lett 338:89-93
Garcia, Orquidea; Carraro, Gianni; Turcatel, Gianluca et al. (2013) Amniotic fluid stem cells inhibit the progression of bleomycin-induced pulmonary fibrosis via CCL2 modulation in bronchoalveolar lavage. PLoS One 8:e71679
Driscoll, Barbara; Kikuchi, Alex; Lau, Allison N et al. (2012) Isolation and characterization of distal lung progenitor cells. Methods Mol Biol 879:109-22
Garcia, Orquidea; Buckley, Sue; Navarro, Sonia et al. (2012) Modulating the alveolar milieu to enhance resolution of fibrotic lung injury. Proc Am Thorac Soc 9:117-9
Jackson, Sha-Ron; Lee, Jooeun; Reddy, Raghava et al. (2011) Partial pneumonectomy of telomerase null mice carrying shortened telomeres initiates cell growth arrest resulting in a limited compensatory growth response. Am J Physiol Lung Cell Mol Physiol 300:L898-909
Buckley, Susan; Shi, Wei; Carraro, Gianni et al. (2011) The milieu of damaged alveolar epithelial type 2 cells stimulates alveolar wound repair by endogenous and exogenous progenitors. Am J Respir Cell Mol Biol 45:1212-21
Lee, Jooeun; Reddy, Raghava; Barsky, Lora et al. (2009) Lung alveolar integrity is compromised by telomere shortening in telomerase-null mice. Am J Physiol Lung Cell Mol Physiol 296:L57-70
Lee, Jooeun; Reddy, Raghava; Barsky, Lora et al. (2006) Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia. Am J Physiol Lung Cell Mol Physiol 290:L685-L694
Reddy, Raghava; Buckley, Sue; Doerken, Melissa et al. (2004) Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells. Am J Physiol Lung Cell Mol Physiol 286:L658-67