Mechanisms of Teleomere-Mediated Emphysema

描述（由申请人提供）：肺气肿在美国和世界范围内造成巨大的健康负担。吸烟和高龄是其发展的最大危险因素，但导致肺气肿易感性的遗传因素及其与年龄相关的发病在很大程度上是未知的。端粒是保护染色体末端的DNA和蛋白质结构。每当细胞分裂时，端粒就会缩短，短端粒会激活DNA损伤反应，从而引发细胞死亡或细胞周期停滞。端粒长度在人群中是异质的，随着年龄的增长而缩短；但是端粒和肺气肿之间的联系还没有在动物模型中被探索过。这项提议建立在令人兴奋的初步数据的基础上，这些数据表明，端粒较短的小鼠更容易受到香烟烟雾（CS）的影响，并患上肺气肿。我们发现短端粒限制了肺上皮细胞损伤后的修复和恢复能力。本项目将以端粒功能失调的小鼠为模型系统，研究肺气肿生物学，探索其发病机制。在第一个目标中，我们将从基因上去除DNA损伤后细胞周期阻滞的一个关键下游调节因子，并测试这是否能挽救端粒诱导的CS易感性。在第二个目标中，我们将建立一个新的模型来探索端粒功能障碍在肺内个体细胞类型中的后果，以确定肺气肿易感性的细胞基础。最后，在第三个目标中，我们将考察

DESCRIPTION (provided by applicant): Emphysema causes an enormous health burden within the United States and worldwide. Smoking and advanced age are the biggest risk factors for its development, yet the genetic factors that contribute to emphysema susceptibility and its associated age-related onset are largely unknown. Telomeres are DNA and protein structures that protect the ends of chromosomes. Each time a cell divides, telomeres shorten and short telomeres activate a DNA damage response that triggers cell death or cell cycle arrest. Telomere lengths are heterogeneous in the population and shorten with age; but the link between telomeres and emphysema has not been explored in animal models. This proposal builds on exciting preliminary data we have generated that mice with short telomeres are more susceptible to cigarette smoke (CS) and develop emphysema. We have found that short telomeres limit the ability of lung epithelial cells to repair and recover after injury. This projet will use mice with dysfunctional telomeres as a model system for studying emphysema biology and explore mechanisms that underlie its pathogenesis. In the first aim, we will genetically remove a key downstream regulator of cell cycle arrest following DNA damage and test if this rescues telomere-induced CS susceptibility. In the second aim, we will generate a new model to probe the consequences of telomere dysfunction in individual cell types within the lung to define the cellular basis for the emphysema susceptibility. Finally, in the third aim, we will examine the secreted proteins that mediate telomere-induced lung restructuring; this is the subject of the independent portion of this research. The proposed studies have potential to identify key pathways that contribute to emphysema pathogenesis. When identified, these mediators could potentially be targeted to treat or prevent emphysema. I have chosen an outstanding environment and group of mentors to complete the final years of my training. During the training period, I anticipate that the environment and additional training plan I have formulated will prepare me to establish an independent group that can make significant advances in translational lung research.