The Role of Short Telomeres in Emphysema Pathogenesis

描述(申请人提供)：端粒完整性对细胞和器官功能至关重要。在存在短端粒的情况下，细胞激活DNA损伤反应，发出凋亡和衰老的信号。临床上，这些细胞程序表现为进行性、退行性器官衰竭。由于短端粒随着年龄的增长而积累，即使在端粒酶是野生型的情况下也会损害组织修复，因此它们被认为与介导年龄相关的疾病有关。然而，肺中端粒缩短的后果还不完全清楚。除了吸烟，年龄是患肺气肿的最大风险因素。肺气肿的发病率随着年龄的增长而稳步增加，是美国第四大最常见的死亡原因。然而，导致与年龄相关的肺气肿增加的遗传机制并不完全清楚。这项建议在一个相关的和基因定义的模型--端粒酶基因敲除小鼠中研究了短端粒在肺气肿易感性和发病机制中的作用。我们假设，短端粒与吸烟相关的DNA损伤协同作用，导致分子缺陷，从而引发肺气肿表型。鉴于最近的观察表明，在吸烟者中，短端粒与肺气肿表型相关，了解短端粒在肺气肿发病机制中的作用尤为重要。因此，建议的研究有可能促进对与衰老相关的遗传因素的了解，这些因素介导了肺气肿的表型。 公共卫生相关性：该项目研究了端粒短小在慢性阻塞性肺疾病发病机制中的作用，以及端粒缩短可能是肺气肿易感因素的机制。

DESCRIPTION (provided by applicant): Telomere integrity is essential for cell and organ function. In the presence of short telomeres, cells activate a DNA damage response that signals apoptosis and senescence. Clinically, these cellular programs manifest as progressive, degenerative organ failure. Because short telomeres accumulate with aging and impair tissue repair even when telomerase is wildtype, they have been implicated in mediating age-related disease. However, the consequences of telomere shortening in the lung are not fully understood. Aside from cigarette smoke exposure, age is the biggest risk factor for the development of emphysema. Emphysema incidence increases steadily with age and accounts for the fourth most common cause of mortality in the United States. The genetic mechanisms that lead to the age-related increase in emphysema are however not fully known. This proposal examines the role of short telomeres in emphysema susceptibility and pathogenesis in a relevant and genetically defined model, the telomerase knockout mouse. We hypothesize that short telomeres cooperate with cigarette smoke-related DNA damage to induce molecular defects that provoke the emphysema phenotype. Understanding the role of short telomeres in emphysema pathogenesis is particularly significant given recent observations that, in cigarette smokers, short telomeres are associated with the emphysema phenotype. The proposed studies therefore have the potential to advance knowledge about the genetic factors associated with aging that mediate the emphysema phenotype. PUBLIC HEALTH RELEVANCE: This project examines the role of short telomeres in the pathogenesis of chronic obstructive pulmonary disease and the mechanism by which telomere shortening may be a susceptibility factor in emphysema.