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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.

项目概要慢性阻塞性肺疾病（COPD）是美国第三大死亡原因，其特征是响应有害刺激（例如香烟烟雾）而导致不可逆的呼气气流受限。肺气肿伴有气腔破坏性扩大，是 COPD 的一个重要表型，它导致对于高死亡率。越来越多的证据表明 DNA 损伤和肺上皮细胞具有致病作用肺气肿发病机制中的细胞凋亡。然而，香烟烟雾引起的 DNA 损伤的分子基础和细胞凋亡仍有待阐明。我们的基因组和功能研究发现 TACC2 编码中心体相互作用蛋白作为 COPD 候选基因。我们新颖的初步数据表明与没有 COPD 的吸烟者相比，患有 COPD 的吸烟者的 TACC2 显着下降。我们还观察到与 Tacc2+/+ 小鼠相比，Tacc2-/- 小鼠在暴露于香烟烟雾时表现出肺气肿变化并伴有DNA损伤。 TACC2敲除损害同源重组，并增强香烟的作用烟雾诱导的永生化人支气管上皮细胞 (HBEC) 的 DNA 损伤和细胞毒性。卷烟烟雾通过泛素-蛋白酶体途径显着降低 TACC2 蛋白。事实上，促凋亡，泛素 E3 连接酶亚基，称为 F 盒 L7 (FBXL7)，以 TACC2 为目标，使其在细胞中降解。此外， TACC2 被发现与毛细血管扩张共济失调突变 (ATM) 相关，ATM 是一种关键的 DNA 损伤感应激酶，并且这种联想受到香烟烟雾的刺激。这些初步数据使我们得出了一个总体假设香烟烟雾通过 TACC2 依赖性诱导 ATM 介导的 DNA 损伤反应 COPD 中的这一机制受损，导致肺上皮细胞凋亡和肺气肿的形成。在目标 1 中，我们将确定 TACC2 是否通过 ATM 发挥作用来控制香烟烟雾引起的 DNA 损伤肺上皮细胞的反应和细胞毒性。在目标 2 中，我们将确定 ATM 是否依赖 TACC2 的磷酸化促进其 FBXL7 介导的香烟烟雾暴露肺上皮细胞的降解细胞。在目标 3 中，我们将确定增加的 TACC2 稳定性是否可以防止香烟烟雾引起的 DNA 损伤反应、肺上皮细胞凋亡和肺气肿。完成拟议的研究将阐明吸烟引起的 COPD 肺部 DNA 损伤积累的机制，并有可能导致开发出一种针对这种使人衰弱的疾病的新治疗方法。