Mechanisms of Telomere-Mediated Lung Disease

摘要 与年龄相关的肺部疾病，包括慢性阻塞性肺疾病(COPD)和特发性 肺纤维化(IPF)，是一种限制呼吸能力的破坏性疾病，是导致 给我们国家的医疗保健系统带来了巨大的负担。这些疾病基本上没有治疗方法。 除了肺移植。高龄是COPD和PF的重要危险因素，但它如何 导致疾病的发病机制尚不清楚。最近，与端粒有关的基因突变 维护已被认为是导致IPF的最常见的可识别原因，在很大程度上 慢性阻塞性肺疾病（慢阻肺）。这一发现为理解肺部疾病提供了一个新的框架，并可能为 衰老。 端粒是位于每条染色体末端的DNA蛋白质帽，起着生物时钟的作用。 端粒随着年龄的增长而缩短，当它们变得太短时，它们会引发细胞衰老(永久细胞 周期拘禁)或死亡。出乎意料的是，肺是最常受到短端粒和 导致肺部疾病的机制尚不清楚。我们已经开发出一种新的老鼠模型，可以 诱导肺内特定细胞类型的端粒功能障碍。当被触发时，端粒故障会导致 肺上皮细胞的衰老，而不是凋亡。因为衰老细胞的比例随着 我们衰老，这个模型提供了一个机会来研究衰老在特定细胞和组织中的后果。 这项建议旨在探索端粒功能障碍和随后的细胞 衰老会导致肺部疾病。我们将从三个相关的方面剖析细胞衰老的后果 目标。在每个目标中，我们检查了细胞衰老的不同方面对肺部生物学的影响。在目标1中，我们将 研究抑制细胞增殖对肺上皮细胞的影响，并检查它们是否可以 有助于肺切除后的肺再生。在目标2中，我们将描述分泌的蛋白质 通过衰老的上皮细胞，确定它们在慢性炎症中的作用。我们还将测试他们是否 存在于临床IPF样本中。最后，在目标3中，我们将确定端粒功能障碍和衰老是否 足以导致肺上皮细胞线粒体功能障碍。我们希望这些数据不仅会 有助于我们理解肺部疾病，但也提出了治疗它的新方法。

Abstract Age associated lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), are devastating diseases that limit respiratory capacity and are responsible for an enormous burden on our country’s health care system. There are essentially no treatments for these diseases except for lung transplantation. Advanced age is a significant risk factors for COPD and PF yet how it contributes to disease pathogenesis is not known. Recently, mutations in the genes responsible for telomere maintenance have been recognized as the most common identifiable cause of IPF and a significant fraction COPD. This discovery provides a new framework for understanding lung disease and may provide a link to aging. Telomeres are DNA-protein caps on the ends of each of chromosomes that function as biologic clocks. Telomeres shorten with age and when they become too short, they trigger cellular senescence (permanent cell cycle arrest) or death. Unexpectedly, the lung is the organ most frequently affected by short telomeres and the mechanisms that lead to lung disease are not known. We have developed a novel mouse model that permits induction of telomere dysfunction in specific cell-types within the lung. When triggered, telomere failure leads to senescence, rather than apoptosis, in lung epithelial cells. Because the fraction of senescent cells increases as we age, this model provides an opportunity to examine the consequences of aging in specific cells and tissues. This proposal aims to explore the mechanisms by which telomeres dysfunction and subsequent cellular senescence cause lung disease. We will dissect the consequences of cellular senescence in three related aims. In each aim, we examine different aspects of cellular senescence on lung biology. In Aim 1, we will investigate the consequences of inhibited cell proliferation on lung epithelial cells and examine if they can contribute to lung regeneration after pneumonectomy. In Aim 2, we will characterize proteins that are secreted by senescent epithelial cells and determine their role in chronic inflammation. We will also test if they are present in clinical IPF samples. Finally, in Aim 3, we will determine if telomere dysfunction and senescence are sufficient to cause mitochondrial dysfunction in the lung epithelium. We hope that these data will not only contribute to our understanding of lung disease, but also suggest novel approaches to treating it.