The Role of Short Telomeres in Emphysema Pathogenesis

描述（由申请人提供）：端粒完整性对细胞和器官功能至关重要。在短端粒的存在下，细胞激活DNA损伤反应，发出细胞凋亡和衰老的信号。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，即使端粒酶是野生型也会损害组织修复，因此它们与介导年龄相关疾病有关。然而，肺中端粒缩短的后果尚未完全了解。除了吸烟暴露外，年龄是肺气肿发展的最大风险因素。肺气肿的发病率随着年龄的增长而稳步增加，在美国是第四大常见的死亡原因。然而，导致与年龄相关的肺气肿增加的遗传机制尚不完全清楚。本研究的目的是在一个相关的基因定义的模型--端粒酶基因敲除小鼠中，研究短端粒在肺气肿易感性和发病机制中的作用。我们假设短端粒与香烟烟雾相关的DNA损伤合作，诱导引发肺气肿表型的分子缺陷。了解短端粒在肺气肿发病机制中的作用特别重要，因为最近的观察表明，在吸烟者中，短端粒与肺气肿表型相关。因此，拟议中的研究有可能推进与衰老相关的遗传因素介导肺气肿表型的知识。 公共卫生相关性：本项目研究端粒短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.