Role of DNA Repair in COPD

DNA 修复在 COPD 中的作用

基本信息

批准号：
9272778
负责人：
Toru Nyunoya
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
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/9272778
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 Impairment In Vitro Intervention Knock-out Lead Lung Messenger RNA Mus Pathogenesis Pathway interactions Patient Recruitments Patients Phenotype Predisposition Proteins Pulmonary Emphysema 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

项目摘要

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）：吸烟是肺肺气肿的主要危险因素，肺气肿是慢性阻塞性肺部疾病（COPD）的关键表型。但是，尚不清楚为什么尽管停止戒烟，肺气肿仍然持续。新兴证据表明，由于DNA修复功能不全，持续性DNA损伤的潜在作用。我们新的初步数据确定DNA修复基因XRCC5的蛋白质表达显着降低，并与COPD患者肺中泛素相关的修饰剂偶联（Sumoylation）增加有关。香烟烟雾提取物（CSE）显着降低了原代人支气管上皮细胞（HBEC）中的XRCC5蛋白，而不是mRNA。 XRCC5表达的抑制增强了永生的HBEC中CSE诱导的细胞毒性和DNA损伤（？H2AX）。相比之下，XRCC5过表达减弱了CSE效应。此外，XRCC5的半合子缺乏响应香烟烟雾（CS）和流感病毒（IAV）感染，增强了肺气肿。这些初步数据使我们提出了一个总体假设，即CS诱导的临界修复蛋白XRCC5的耗竭有助于持续的DNA损伤和肺气肿的形成。在AIM 1中，我们将确定与没有COPD的前吸烟者相比，具有COPD的前吸烟者的肺是否显示出XRCC5损失和DNA损伤。在AIM 2中，将研究CS诱导的体外XRCC5耗竭的机制。在AIM 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转基因小鼠对XRCC5进行功能丧失和功能障碍研究。通过实现这些目标，我们将加深对DNA修复在COPD发病机理中作用的理解。这些发现可能通过增强DNA修复（例如XRCC5）来导致新型治疗剂的发展，从而调节对CS诱导的肺气肿的敏感性。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PP2A as a New Player in Chronic Obstructive Pulmonary Disease.

PP2A 作为慢性阻塞性肺疾病的新参与者。

DOI：
10.1165/rcmb.2018-0242ed
发表时间：
2018
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
Li,Xiuying;Nyunoya,Toru
通讯作者：
Nyunoya,Toru

A Novel Compound, "FA-1" Isolated from Prunus mume, Protects Human Bronchial Epithelial Cells and Keratinocytes from Cigarette Smoke Extract-Induced Damage.

从梅花中分离出的一种新型化合物“FA-1”可保护人支气管上皮细胞和角质形成细胞免受香烟烟雾提取物引起的损伤。

DOI：
10.1038/s41598-018-29701-2
发表时间：
2018-07-31
期刊：
Scientific reports
影响因子：
4.6
作者：
Jang AJ;Lee JH;Yotsu-Yamashita M;Park J;Kye S;Benza RL;Passineau MJ;Jeon YJ;Nyunoya T
通讯作者：
Nyunoya T