Role of WRN Protein in Cigarette Smoke-Induced Cellular Senescence and Emphysema.

WRN 蛋白在香烟烟雾诱导的细胞衰老和肺气肿中的作用。

• 批准号: 7962245
• 负责人: Toru Nyunoya
• 金额: $ 5.18万
• 依托单位: BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7962245
• 关键词: Age; Aging; Aging-Related Process; Alveolar; Biological; Cell Aging; Cell Proliferation; Cells; Cessation of life; Cigarette smoke-induced emphysema; Databases; Defect; Dermal; Disease; Down-Regulation; Epithelial Cells; Exhibits; Exposure to; Family; Fibroblasts; Genes; Genome; Genomic Instability; Glutamic Acid; Hereditary Disease; Human; Inherited; Knock-out; Knockout Mice; Link; Lung; Malignant Neoplasms; Modeling; Molecular; Mus; Pathway interactions; Patients; Phenotype; Physiological; Predisposition; Premature aging syndrome; Proline; Pulmonary Emphysema; RNA Interference; Regulation; Research; Role; Serine; Signaling Protein; Smoke; Smoker; System; Testing; Threonine; Time; Ubiquitin; Werner Syndrome; Wound Healing; airway obstruction; base; cell type; cigarette smoke-induced; cigarette smoking; cigarette smoking; helicase; human WRN protein; loss of function mutation; member; multicatalytic endopeptidase complex; novel; novel therapeutics; polypeptide; premature; protein degradation; protein expression; public health relevance; senescence; tool

DESCRIPTION (provided by applicant): Aging contributes to lung emphysema and progressive airway obstruction due to decreased elastic recoil. The aging process is also associated with cellular senescence-a state in which cells are metabolically active, but permanently unable to divide. Cigarette smoking is a major cause of lung emphysema by accelerating the aging process with resultant premature death due to atherosclerotic diseases and malignancy. Werner's syndrome, a genetic disorder caused by loss-of-function mutations in the Wrn gene encoding a member of RecQ helicase family (WRN protein), also accelerates aging. Both cigarette smoke and WRN protein defects induce cellular senescence. However, there have been no studies that investigate the potential link between cigarette smoke-induced accelerated aging and Werner's syndrome. I recently demonstrated that cigarette smoke induces cellular senescence via WRN protein downregulation in cultured human lung fibroblasts. I also showed that cigarette smoke decreases WRN protein in an ubiquitin-proteasome dependent pathway. The unique polypeptide sequences enriched in proline (P), glutamic acid (E), serine (S) and threonine (T) (PEST) residues are often targeted for protein degradation. By database analysis, I identified that WRN protein harbors three high value PEST targets. My proposed research will further investigate molecular mechanisms of cigarette smoke-induced cellular senescence via reducing WRN protein stability. My central hypothesis is that WRN protein stability serves as a critical mechanism that alters lung susceptibility to smoking-induced emphysema. In Aim1, I will investigate the role of PEST sequences in cigarette smoke-induced WRN protein degradation and cellular senescence. In Aim2, I will determine if WRN protein defects alter the effects of cigarette smoke on cellular senescence and emphysema by using Wrn knock-out mice. This proposal will help to understand the potential role of WRN protein in smoking-induced emphysema and may contribute to novel therapeutic strategies directed at modulating WRN protein expression. PUBLIC HEALTH RELEVANCE: We have recently demonstrated for the first time that cigarette smoke induces cellular senescence via Werner's syndrome protein downregulation in cultured lung fibroblasts. We have also demonstrated that cigarette smoke enhances WRN protein degradation in a ubiquitin-proteasome dependent manner. We propose in this application to identify the molecular mechanisms for WRN protein degradation after cigarette smoke exposure and to further investigate a role or WRN protein in cigarette smoke-induced cellular senescence and emphysema by using a murine model.

描述（由申请人提供）：由于弹性回缩力降低，衰老会导致肺气肿和进行性气道阻塞。衰老过程还与细胞衰老有关，细胞衰老是一种细胞代谢活跃但永久无法分裂的状态。吸烟是导致肺气肿的主要原因，它会加速衰老过程，导致动脉粥样硬化性疾病和恶性肿瘤导致过早死亡。沃纳氏综合症是一种由编码 RecQ 解旋酶家族成员（WRN 蛋白）的 Wrn 基因功能丧失突变引起的遗传性疾病，也会加速衰老。香烟烟雾和 WRN 蛋白缺陷都会导致细胞衰老。然而，目前还没有研究调查吸烟引起的加速衰老与维尔纳综合症之间的潜在联系。我最近证明，香烟烟雾通过培养的人肺成纤维细胞中 WRN 蛋白下调诱导细胞衰老。我还表明，香烟烟雾会降低泛素蛋白酶体依赖性途径中的 WRN 蛋白。富含脯氨酸 (P)、谷氨酸 (E)、丝氨酸 (S) 和苏氨酸 (T) (PEST) 残基的独特多肽序列通常是蛋白质降解的目标。通过数据库分析，我发现 WRN 蛋白具有三个高价值的 PEST 靶标。我提出的研究将通过降低 WRN 蛋白稳定性来进一步研究香烟烟雾诱导细胞衰老的分子机制。我的中心假设是 WRN 蛋白稳定性是改变肺部对吸烟引起的肺气肿的易感性的关键机制。在 Aim1 中，我将研究 PEST 序列在香烟烟雾诱导的 WRN 蛋白降解和细胞衰老中的作用。在 Aim2 中，我将通过使用 Wrn 敲除小鼠来确定 WRN 蛋白缺陷是否会改变香烟烟雾对细胞衰老和肺气肿的影响。该提议将有助于了解 WRN 蛋白在吸烟引起的肺气肿中的潜在作用，并可能有助于制定针对调节 WRN 蛋白表达的新治疗策略。 公共健康相关性：我们最近首次证明，香烟烟雾通过培养的肺成纤维细胞中维尔纳综合征蛋白下调诱导细胞衰老。我们还证明，香烟烟雾以泛素蛋白酶体依赖性方式增强 WRN 蛋白降解。我们在本申请中建议确定香烟烟雾暴露后 WRN 蛋白降解的分子机制，并通过使用小鼠模型进一步研究 WRN 蛋白在香烟烟雾诱导的细胞衰老和肺气肿中的作用。