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致残和死亡的主要原因。除了吸烟，年龄是肺气肿发展的最大危险因素。有些人认为肺气肿是一种与年龄有关的疾病，因为肺泡破坏是肺气肿的标志，它发生在正常的衰老肺中。端粒功能障碍是细胞衰老最具特征的机制之一。我们的小组最近表明，端粒功能障碍是小鼠以及一些人类家庭中肺气肿易感性的决定因素。该应用程序建立在这些发现的基础上，探讨了端粒介导的肺气肿机制。我们的重点主要是了解上皮损伤和细胞衰老如何随着年龄的增长和对吸烟的反应而导致肺气肿。具体目的建立在令人信服的数据上，这些数据显示上皮细胞的端粒功能障碍限制了损伤后的修复，并测试端粒长度是否与肺泡祖细胞干细胞功能有关。我们提出的研究旨在在衰老机制的背景下推进肺气肿生物学的范式，以确定对疾病机制的新认识和新的治疗靶点。

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.