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危险因素。一些人认为肺气肿是一种与年龄有关的疾病，因为作为其标志的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的最佳表征机制之一。我们的研究小组最近发现，端粒功能障碍是小鼠和一些人类家族中肺气肿易感性的决定因素。本申请建立在这些发现的基础上，以探讨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如何导致肺气肿，随着年龄的增长和对香烟烟雾的反应。具体目标建立在令人信服的数据表明，上皮细胞中的端粒功能障碍限制损伤后的修复，并测试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。我们提出的研究旨在推进肺气肿生物学在衰老机制背景下的范例，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.