Role of TACC2 in smoking-induced COPD

TACC2 在吸烟诱发的 COPD 中的作用

基本信息

批准号：
10338145
负责人：
Toru Nyunoya
金额：
$ 39.25万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338145
关键词：
Alveolar wall Apoptosis Candidate Disease Gene Cause of Death Cell Cycle Cell Death Cell Survival Cell Wall Cell physiology Cells Centrosome Chronic Obstructive Pulmonary Disease DNA DNA Damage Data Databases Development Disease Distal Economic Burden Epithelial Cells Exhibits F Box Domain Genes Genomics Human Impairment Inhalation Lead Link Lung Lung diseases Mediating Microtubule-Associated Proteins Microtubules Modeling Molecular Mus Mutation Pathogenesis Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Protein-Serine-Threonine Kinases Proteins Pulmonary Emphysema Regulation Resistance Respiration Disorders Role Signal Transduction Site Smoker Smoking Stimulus System TACC2 gene Terminal Bronchiole Testing Ubiquitin Ubiquitination United Kingdom United States airway obstruction alveolar epithelium ataxia telangiectasia mutated protein base biobank bronchial epithelium cigarette smoke cigarette smoke-induced cytotoxicity exposure to cigarette smoke homologous recombination knock-down mortality mouse model multicatalytic endopeptidase complex mutant novel novel therapeutic intervention prevent recombinational repair repaired response segregation single-cell RNA sequencing spatiotemporal ubiquitin-protein ligase

项目摘要

Project Summary Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is characterized by irreversible expiratory airflow limitation in response to noxious stimuli (e.g., cigarette smoke). Emphysema, with destructive enlargement of the airspaces, is an important phenotype of COPD that accounts for high mortality rates. Accumulating evidence suggest a causative role of DNA damage and lung epithelial cell apoptosis in emphysema pathogenesis. However, the molecular basis for cigarette smoke-induced DNA damage and apoptosis remains to be elucidated. Our genomic and functional studies identified TACC2 that encodes a centrosome-interacting protein as a COPD candidate gene. Our novel preliminary data demonstrate that smokers with COPD exhibit a marked decrease in TACC2 relative to smokers without COPD. We also observed that Tacc2-/- compared to Tacc2+/+ mice when exposed to cigarette smoke exhibit emphysematous changes accompanied by DNA damage. TACC2 knockdown impairs homologous recombination, and augments cigarette smoke-induced DNA damage and cytotoxicity in immortalized human bronchial epithelial cells (HBEC). Cigarette smoke significantly reduces TACC2 protein via the ubiquitin-proteasome pathway. Indeed, a proapoptotic, ubiquitin E3 ligase subunit, termed F box L7 (FBXL7), targets TACC2 for its degradation in cells. Furthermore, TACC2 is found to associate with ataxia telangiectasia mutated (ATM), a key DNA damage-sensing kinase, and the association is stimulated by cigarette smoke. These preliminary data led us to an overarching hypothesis that cigarette smoke induces the ATM-mediated DNA damage response through a TACC2-dependent mechanism that is impaired in COPD, leading to lung epithelial cell apoptosis and the formation of emphysema. In Aim 1, we will determine whether TACC2 acts through ATM to control cigarette smoke-induced DNA damage response and cytotoxicity in lung epithelial cells. In Aim 2, we will determine whether ATM-dependent phosphorylation of TACC2 promotes its FBXL7-mediated degradation in cigarette smoke-exposed lung epithelial cells. In Aim 3, we will determine whether increased TACC2 stability protects against cigarette smoke-induced DNA damage response, lung epithelial cell apoptosis, and emphysema. Completion of the proposed studies will elucidate the mechanisms of smoking-induced DNA damage accumulation in COPD lungs and will potentially lead to development of a novel therapeutic approach for this debilitating disease.

项目摘要慢性阻塞性肺疾病（COPD）是美国第三大死亡原因，是响应有害刺激（例如香烟烟）的不可逆转的呼气限制的特征。肺气肿具有破坏性的空间扩大，是COPD的重要表型对于高死亡率。积累的证据表明DNA损伤和肺上皮细胞的病因作用肺气肿发病机理中的凋亡。但是，香烟烟雾引起的DNA损伤的分子基础凋亡仍有待阐明。我们的基因组和功能研究确定了编码A的TACC2 中心体相互作用蛋白作为COPD候选基因。我们的小说初步数据表明相对于没有COPD的吸烟者，患有COPD的吸烟者显示出TACC2的明显减少。我们也观察到与Tacc2+/+小鼠相比，tacc2 - / - 暴露于香烟烟雾时表现出多重变化伴随着DNA损伤。 TACC2敲低会损害同源重组，并增强香烟永生的人支气管上皮细胞（HBEC）中烟雾诱导的DNA损伤和细胞毒性。卷烟烟雾通过泛素 - 蛋白酶体途径可显着降低TACC2蛋白。确实，凋亡，泛素E3连接酶亚基称为F Box L7（FBXL7），其靶向TACC2的细胞降解。此外，发现TACC2与共济失调的毛细血管炎突变（ATM），关键DNA损伤激酶和该协会被香烟烟雾刺激。这些初步数据导致我们提出了一个总体假设这种香烟烟通过TACC2依赖性诱导ATM介导的DNA损伤反应 COPD中受损的机制，导致肺上皮细胞凋亡和肺气肿的形成。在AIM 1中，我们将确定TACC2是否通过ATM作用以控制烟雾引起的DNA损伤肺上皮细胞中的反应和细胞毒性。在AIM 2中，我们将确定ATM依赖性是否依赖 TACC2的磷酸化促进了其FBXL7介导的烟雾暴露于肺上皮的降解细胞。在AIM 3中，我们将确定提高TACC2稳定性是否可以防止吸烟引起的烟雾 DNA损伤反应，肺上皮细胞凋亡和肺气肿。拟议研究的完成将阐明吸烟引起的DNA损伤在COPD肺中积累的机制，并有可能导致为这种使人衰弱的疾病开发一种新型的治疗方法。