Mechanisms of DNA damage induced emphysema

摘要 这一更新应用旨在了解肺气肿易感性的遗传决定因素。 肺气肿-慢性阻塞性肺疾病(COPD)在美国至少影响1000万人， 是世界各地死亡和残疾的主要原因。在吸烟者中，只有10%-15%的COPD和 已知遗传因素导致了这种易感性。在之前的资助期间，我们发现了突变 端粒酶基因是家族性和早发性肺气肿的第二个孟德尔病因 抗胰蛋白酶缺乏症。我们记录了女性吸烟者的特定嗜好，她们占突变的90%。 端粒酶相关性肺气肿。在动物模型中，我们确定肺泡干细胞衰老是驱动因素 肺泡破坏和炎症。对于此续订申请，我们重点了解基因 DNA损伤的缺陷，除了端粒功能障碍，还会导致肺气肿的生物学和易感性。我们 已经确定了一种新的动物模型，在该模型中，暴露于基因毒性损害的女性会患上肺部疾病，但 不是男性。在拟议的实验中，我们将前瞻性地检查男性和女性在吸烟方面的差异 吸烟易感性并将DNA修复缺陷确定为人类的一个危险因素 肺气肿。我们的提案中对性别差异的关注特别及时，因为有证据表明 在其他地方，这一现象预计还会增加，因为#年香烟吸烟率仍在上升 女人。因此，拟议的研究有可能填补对肺气肿生物学和 并阐明肺气肿外显性的性别差异。

Abstract This renewal application aims to understand the genetic determinants of emphysema susceptibility. Emphysema-chronic obstructive disease (COPD) affect at least 10 million individuals in the United States and are a major cause of mortality and disability around the world. Among smokers, only 10-15% COPD and genetic factors are known to contribute to this susceptibility. In the prior funding period, we identified mutant telomerase genes as a second Mendelian cause of familial and early-onset emphysema beyond alpha-1 antitrypsin deficiency. We documented a specific predilection in female smokers who comprised 90% of mutant telomerase-associated emphysema. In animal models, we identified alveolar stem cell senescence as a driver of alveolar destruction and inflammation. For this renewal application, we focus on understanding how genetic defects in DNA damage, beyond telomere dysfunction, contribute to emphysema biology and susceptibility. We have identified a new animal model in which females exposed to genotoxic damage develop lung disease but not males. For the proposed experiments, we will prospectively examine male-female differences in cigarette smoke susceptibility and define the contribution of defective DNA repair as a risk factor for human emphysema. The focus on sex differences in our proposal is particularly timely since there is evidence that elsewhere, and this phenomenon is expected to grow since cigarette smoke rates remain on the rise in women. The proposed therefore have the potential to fill gaps in understanding emphysema biology and susceptibility and to shed light on sex-specific differences of emphysema penetrance in a context of significant