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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）：

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）

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

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。