Role of DNA Repair in COPD

DNA 修复在 COPD 中的作用

• 批准号: 9000005
• 负责人: Toru Nyunoya
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000005
• 关键词: Alveolar; Alveolar Cell; Apoptosis; Attenuated; Cause of Death; Cell Aging; Cell Proliferation; Cells; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Disorder; DNA Repair Gene; Data; Development; Disease; Disease Progression; Double Strand Break Repair; Economic Burden; Epithelial Cells; Excision; Exhibits; High Prevalence; Human; In Vitro; Intervention; Knock-out; Lead; Lung; Messenger RNA; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Predisposition; Proteins; Pulmonary Emphysema; Recruitment Activity; Respiratory Signs and Symptoms; Respiratory physiology; Risk; Risk Factors; Role; Site; Smoker; Telomere Maintenance; Testing; Transgenic Mice; Ubiquitin; Veterans; Virus Diseases; XRCC5 gene; cigarette smoke-induced; cigarette smoking; cigarette smoking; cytotoxicity; gain of function; improved; in vivo; influenzavirus; insight; loss of function; mortality; novel; novel therapeutics; overexpression; protein expression; protein function; public health relevance; repaired; response; smoking cessation; telomere; wound

DESCRIPTION (provided by applicant): Cigarette smoking is the major risk factor for pulmonary emphysema, a critical phenotype of chronic obstructive pulmonary disease (COPD). However, it remains unclear why emphysema persists despite smoking cessation. Emerging evidence suggests a potential role of persistent DNA damage due to DNA repair insufficiency. Our novel preliminary data determined that protein expression of the DNA repair gene XRCC5 is markedly reduced and associated with increased small ubiquitin-related modifier conjugation (SUMOylation) in the lungs of patients with COPD. Cigarette smoke extract (CSE) significantly decreased XRCC5 protein, but not mRNA, in primary human bronchoepithelial cells (HBECs). Suppression of XRCC5 expression augmented CSE-induced cytotoxicity and DNA damage (?H2AX) in immortalized HBECs. By contrast, XRCC5 overexpression attenuated the CSE effects. Furthermore, the hemizygous deficiency of XRCC5 augmented emphysema in response to cigarette smoke (CS) and influenza virus (IAV) infection. These preliminary data led us to an overarching hypothesis that CS-induced depletion of the critical repair protein, XRCC5, contributes to persistent DNA damage and the formation of emphysema. In Aim 1, we will determine whether the lungs of ex-smokers with COPD exhibit XRCC5 loss and DNA damage compared with ex-smokers without COPD. In Aim 2, the mechanisms of CS-induced depletion of XRCC5 in vitro will be investigated. In Aim 3, to determine whether XRCC5 protein expression modulates CS-induced DNA damage and emphysema, we will execute loss-of-function and gain-of-function studies of XRCC5 in vivo using XRCC5+/- and XRCC5 transgenic mice, respectively. By achieving these aims, we will deepen our understanding of the role of DNA repair in COPD pathogenesis. These findings may lead to the development of novel therapeutics by augmenting DNA repair (e.g., XRCC5) that may modulate susceptibility to CS-induced emphysema.

描述（由申请人提供）： 吸烟是肺气肿的主要危险因素，肺气肿是慢性阻塞性肺病（COPD）的一种关键表型。然而，目前尚不清楚为什么尽管戒烟后肺气肿仍然存在。新出现的证据表明，由于 DNA 修复不足，导致持续性 DNA 损伤具有潜在作用。我们的新初步数据确定，DNA 修复基因 XRCC5 的蛋白表达显着降低，并与 COPD 患者肺部小泛素相关修饰物缀合（SUMOylation）的增加相关。香烟烟雾提取物 (CSE) 显着降低原代人支气管上皮细胞 (HBEC) 中的 XRCC5 蛋白，但不降低 mRNA。 XRCC5 表达的抑制增强了永生化 HBEC 中 CSE 诱导的细胞毒性和 DNA 损伤 (?H2AX)。相比之下，XRCC5 过度表达减弱了 CSE 效应。此外，XRCC5 的半合子缺陷会加剧香烟烟雾 (CS) 和流感病毒 (IAV) 感染引起的肺气肿。这些初步数据使我们得出一个总体假设：CS 诱导的关键修复蛋白 XRCC5 的消耗会导致持续的 DNA 损伤和肺气肿的形成。在目标 1 中，我们将确定患有 COPD 的戒烟者的肺部与未患 COPD 的戒烟者相比是否表现出 XRCC5 丢失和 DNA 损伤。在目标 2 中，将研究 CS 诱导的体外 XRCC5 消耗的机制。在目标 3 中，为了确定 XRCC5 蛋白表达是否调节 CS 诱导的 DNA 损伤和肺气肿，我们将分别使用 XRCC5+/- 和 XRCC5 转基因小鼠在体内进行 XRCC5 功能丧失和功能获得研究。通过实现这些目标，我们将加深对 DNA 修复在 COPD 发病机制中的作用的理解。这些发现可能会导致通过增强 DNA 修复（例如 XRCC5）来开发新疗法，从而调节对 CS 诱导的肺气肿的易感性。