Mechanisms of Telomere-Mediated Lung Disease

摘要

Abstract Age associated lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), are devastating diseases that limit respiratory capacity and are responsible for an enormous burden on our country’s health care system. There are essentially no treatments for these diseases except for lung transplantation. Advanced age is a significant risk factors for COPD and PF yet how it contributes to disease pathogenesis is not known. Recently, mutations in the genes responsible for telomere maintenance have been recognized as the most common identifiable cause of IPF and a significant fraction COPD. This discovery provides a new framework for understanding lung disease and may provide a link to aging. Telomeres are DNA-protein caps on the ends of each of chromosomes that function as biologic clocks. Telomeres shorten with age and when they become too short, they trigger cellular senescence (permanent cell cycle arrest) or death. Unexpectedly, the lung is the organ most frequently affected by short telomeres and the mechanisms that lead to lung disease are not known. We have developed a novel mouse model that permits induction of telomere dysfunction in specific cell-types within the lung. When triggered, telomere failure leads to senescence, rather than apoptosis, in lung epithelial cells. Because the fraction of senescent cells increases as we age, this model provides an opportunity to examine the consequences of aging in specific cells and tissues. This proposal aims to explore the mechanisms by which telomeres dysfunction and subsequent cellular senescence cause lung disease. We will dissect the consequences of cellular senescence in three related aims. In each aim, we examine different aspects of cellular senescence on lung biology. In Aim 1, we will investigate the consequences of inhibited cell proliferation on lung epithelial cells and examine if they can contribute to lung regeneration after pneumonectomy. In Aim 2, we will characterize proteins that are secreted by senescent epithelial cells and determine their role in chronic inflammation. We will also test if they are present in clinical IPF samples. Finally, in Aim 3, we will determine if telomere dysfunction and senescence are sufficient to cause mitochondrial dysfunction in the lung epithelium. We hope that these data will not only contribute to our understanding of lung disease, but also suggest novel approaches to treating it.