Mechanisms of Telomere-Mediated Lung Disease

Abstract Telomere dysfunction has emerged as a primary contributor to diseases within the human lung. Over the past five years, our group has shown that telomere dysfunction limits the proliferative capacity of lung epithelial cells and renders the lung susceptible to injury. In addition, we have found that the senescent lung epithelium secrets a number of bioactive proteins that have unexpected roles in physiology and lung repair. Here we extend our findings to test the centrality of the type II alveolar epithelial cell (AEC2). We build on previous studies that have investigated the roll of AEC2 in disease pathogenesis and repair of the lung epithelium. Our preliminary data support the selective loss of AEC2 with age in humans and extensive loss in the context of disease. Based on these findings, we generated a novel model of chronic AEC2 insufficiency that recapitulates several aspects of idiopathic pulmonary fibrosis (IPF), including a peripheral predilection, depletion of AEC2, and progressive fibrosis that is eventually lethal. This proposal will extend these findings and explore the hypothesis that chronic AEC2 insufficiency is a unifying pathologic mechanism in IPF. In aim 1, we comprehensively and unambiguously map every AEC2 throughout the mouse lifespan including very old mice and examine the changes in spatial organization of AEC2 with injury using a novel whole organ imaging methodology. In aim 2, we characterize a novel model of progressive fibrosis in the mouse that is driven by AEC2 insufficiency. We will examine functional, cellular, and molecular changes throughout development of fibrosis. Aim 3 will test a novel approach to lengthen telomere based on somatic mutations that are acquired in patients with IPF. Together, these aims will test a novel hypothesis that unifies the pathologic mechanisms of IPF and generates new tools and resources for the pulmonary community.