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。

基本信息

批准号：
8150334
负责人：
Toru Nyunoya
金额：
$ 4.98万
依托单位：
BIOMEDICAL RESEARCH INSTITUTE OF NEW MEX
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8150334
关键词：
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 Smoker Smoking 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

项目摘要

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）：衰老有助于肺部肺气肿和由于弹性后坐力减少而导致的渐进性气道阻塞。衰老过程也与细胞衰老-A状态有关，其中细胞是代谢活性的，但无法分裂。吸烟是通过加速衰老过程的肺部肺气肿的主要原因，导致由于动脉粥样硬化疾病和恶性肿瘤而导致过早死亡。 Werner's综合征是由编码RECQ解旋酶家族成员（WRN蛋白）的WRN基因中的功能丧失突变引起的遗传疾病，也加速了衰老。香烟烟雾和WRN蛋白缺陷都会引起细胞衰老。但是，没有研究研究香烟烟雾引起的加速衰老与沃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的WRN蛋白下调诱导细胞衰老。我还表明，在泛素 - 蛋白酶体依赖性途径中，香烟烟雾降低了WRN蛋白。富含脯氨酸（P），谷氨酸（E），丝氨酸（S）和苏氨酸（T）（PEST）残基中的独特多肽序列通常用于蛋白质降解。通过数据库分析，我确定WRN蛋白具有三个高价值害虫靶标。我提出的研究将进一步研究香烟烟雾诱导的细胞衰老的分子机制，通过降低WRN蛋白稳定性。我的中心假设是，WRN蛋白稳定性是改变肺对吸烟引起的肺气肿的敏感性的关键机制。在AIM1中，我将研究虫害序列在烟雾诱导的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蛋白缺陷是否改变了香烟烟雾对细胞衰老和肺气肿的影响。该建议将有助于了解WRN蛋白在吸烟引起的肺气肿中的潜在作用，并可能有助于用于调节WRN蛋白表达的新型治疗策略。公共卫生相关性：最近，我们首次证明了香烟烟雾通过培养的肺成纤维细胞中的Werner综合征蛋白下调引起细胞衰老。我们还证明，香烟烟雾以泛素 - 蛋白酶体的方式增强了WRN蛋白质降解。我们建议在此应用中提出，以确定烟雾烟雾后WRN蛋白降解的分子机制，并通过使用鼠模型进一步研究香烟烟雾诱导的细胞衰老和肺气肿中的作用或WRN蛋白。