The ability to survive lung injury may be due to a specialized sub-population of alveolar epithelial type 2 cells (AEC2) with the capacity to proliferate, repair damaged alveolar epithelium and repopulate the denuded alveolar surface. Recent studies demonstrate that AEC2 that proliferate following oxidative lung injury exhibit a significant increase in telomerase activity and are more resistant to oxidative damage. Fractionation of total AEC2 on the basis of cell surface marker (specifically E-cadherin) expression revealed a discrete subpopulation characterized by upregulated proliferation and telomerase activity, which was also resistant to oxidative injury. The role telomerase plays in the function of this putative progenitor-like sub-population is still to be determined. The hypothesis leading from these observations is: Telomerase plays a central role in determining and maintaining the survivor phenotype of a specialized sub-population of alveolar epithelial progenitor cells that are responsible for repair of damaged alveolar epithelium.
Specific Aims designed to challenge this hypothesis are: 1) To determine if altering telomerase expression and activity in AEC2 in vivo will support or compromise whole animal and AEC2 survival in adults and neonates, 2) To determine if progenitor AEC in which telomerase activity is upregulated can be used to rescue transplanted recipients from hyperoxic damage, and 3) To track and define the role of telomerase in adult progenitor AEC using a model animal in which EGFP is induced by acute lung injury to express solely in TERT positive cells. This work may identify new targets for the design of rational therapies to augment alveolar progenitor cell function in alveolar epithelial regeneration and repair, in both neonatal and adult human alveolar injury.
