Mechanisms of Telomere-Induced Emphysema

描述(由申请人提供)：肺气肿是美国和世界范围内导致残疾和死亡的主要原因。除了吸烟，年龄是肺气肿发展的最大风险因素。肺气肿被一些人认为是一种与年龄相关的疾病，因为它的标志是肺泡破坏，发生在正常老化的肺中。端粒功能障碍是细胞衰老最典型的机制之一。我们的小组最近表明，端粒功能障碍是小鼠和一些人类家庭中肺气肿易感性的决定因素。这项应用建立在这些发现的基础上，以探索端粒介导的肺气肿的机制。我们的重点主要是了解上皮损伤和细胞衰老是如何导致肺气肿的，随着年龄的增长和对香烟烟雾的反应。这些特定的目的建立在令人信服的数据基础上，这些数据表明，上皮细胞中的端粒功能障碍限制了损伤后的修复，并测试了端粒长度是否是肺泡祖细胞中干细胞功能的相关决定因素。我们建议的研究旨在推进衰老机制背景下的肺气肿生物学范式，目的是确定对疾病机制的新理解和新的治疗靶点。

DESCRIPTION (provided by applicant): Emphysema is a leading cause of disability and mortality in the United States and worldwide. Aside from cigarette smoke, age is the biggest risk factor for emphysema development. Emphysema has been considered by some as an age-related disease because the alveolar destruction that is its hallmark occurs in the normal aging lung. Telomere dysfunction is one of the best-characterized mechanisms of cellular aging. Our group has recently shown that telomere dysfunction is a determinant of emphysema susceptibility in mice as well as in some human families. This application builds on these findings to probe the mechanisms underlying telomere-mediated emphysema. Our focus is primarily on understanding how epithelial damage and cellular senescence contribute to emphysema, with age and in response to cigarette smoke. The specific aims build on compelling data showing that telomere dysfunction in epithelial cells limits repair after injury, ad test whether telomere length is a relevant determinant of stem cell function in alveolar progenitor cells. Our proposed studies aim to advance paradigms of emphysema biology in the context of aging mechanisms with the goal of identifying new understanding of disease mechanisms and novel targets for treatment.