Mechanisms of Telomere-Mediated Lung Disease

端粒介导的肺部疾病的机制

• 批准号: 10206235
• 负责人: Jonathan K. Alder
• 金额: $ 38.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206235
• 关键词: Address; Adult; Affect; Age; Aging; Alveolar; Animal Model; Apoptosis; Biological Clocks; Biology; Cause of Death; Cell Aging; Cell Cycle Arrest; Cell Proliferation; Cells; Cessation of life; Chromosomes; Chronic; Chronic Obstructive Airway Disease; Clinical; Country; DNA; DNA Damage; Data; Disease; Elderly; Epithelial; Epithelial Cells; Failure; Functional disorder; Genes; Genetic; Healthcare; Healthcare Systems; Heart; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Lead; Left; Link; Liver; Lung; Lung Transplantation; Lung diseases; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Morphology; Mus; Mutation; Natural regeneration; Organ; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Phenotype; Pneumonectomy; Positioning Attribute; Proteins; Pulmonary Emphysema; Recovery; Regulation; Risk Factors; Role; Sampling; Serum; Signal Transduction; Telomerase; Telomere Maintenance; Telomere Maintenance Gene; Telomere Shortening; Testing; Therapeutic Intervention; Time; Tissues; Toxin; United States; Work; alveolar epithelium; cell type; early onset; endoplasmic reticulum stress; extracellular; idiopathic pulmonary fibrosis; in vivo; lung injury; lung regeneration; lung repair; mitochondrial dysfunction; mouse model; mutation carrier; novel; novel strategies; prevent; progenitor; repaired; respiratory; response; senescence; stem; stem cells; surfactant; telomere; tissue repair

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.

抽象的 与年龄相关的肺部疾病，包括慢性阻塞性肺病 (COPD) 和特发性肺部疾病 肺纤维化 (IPF) 是一种破坏性疾病，会限制呼吸能力并导致 给我国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，但它是如何发生的 导致疾病发病机制尚不清楚。最近，负责端粒的基因发生突变 维护已被认为是 IPF 最常见的可识别原因，并且占很大比例 慢性阻塞性肺病。这一发现为理解肺部疾病提供了一个新的框架，并可能为以下方面提供联系： 老化。 端粒是每条染色体末端的 DNA 蛋白质帽，起到生物钟的作用。 端粒随着年龄的增长而缩短，当它们变得太短时，就会引发细胞衰老（永久细胞） 循环停止）或死亡。出乎意料的是，肺是最常受短端粒影响的器官， 导致肺部疾病的机制尚不清楚。我们开发了一种新颖的小鼠模型，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 肺上皮细胞发生衰老，而不是凋亡。因为衰老细胞的比例随着 随着年龄的增长，该模型提供了一个研究特定细胞和组织衰老后果的机会。 该提案旨在探索端粒功能障碍和随后的细胞损伤的机制。 衰老导致肺部疾病。我们将剖析细胞衰老在三个相关方面的后果 目标。在每个目标中，我们研究了肺生物学中细胞衰老的不同方面。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 有助于肺切除术后的肺再生。在目标 2 中，我们将表征分泌的蛋白质 衰老的上皮细胞并确定它们在慢性炎症中的作用。我们还将测试它们是否是 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与 足以引起肺上皮线粒体功能障碍。我们希望这些数据不仅能够 有助于我们对肺部疾病的理解，同时也提出了治疗肺部疾病的新方法。