Mechanisms of DNA damage induced emphysema

摘要 这个更新申请的目的是了解肺气肿易感性的遗传决定因素。 在美国，肺气肿-慢性阻塞性疾病（COPD）影响至少1000万个体， 是全世界死亡和残疾的主要原因。在吸烟者中，只有10-15%的COPD和 已知遗传因素有助于这种易感性。在上一个融资期，我们发现了突变体， 端粒酶基因是α-1以外家族性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一种特殊偏好， 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一个驱动因素， 肺泡的破坏和炎症。对于这个更新应用程序，我们专注于了解基因如何 DNA损伤的缺陷，除了端粒功能障碍之外，还导致肺气肿生物学和易感性。我们 已经确定了一种新的动物模型，在这种模型中，暴露于遗传毒性损伤的雌性动物会患上肺病， 而不是男性。对于所提议的实验，我们将前瞻性地检查男性和女性在吸烟方面的差异。 吸烟易感性和定义的贡献有缺陷的DNA修复作为一个危险因素， 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，这种现象预计会增加，因为吸烟率仍在上升， 妇女因此，所提出的有可能填补理解肺气肿生物学的空白， 易感性，并揭示了性别特异性差异的肺气肿发病率的背景下，

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