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Role of Werner's Syndrome Protein in Cigarette Smoke-Induced Cellular Senescence

维尔纳综合征蛋白在香烟烟雾诱导的细胞衰老中的作用

基本信息

批准号：
7779961
负责人：
Toru Nyunoya
金额：
$ 5.83万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2010-08-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7779961
关键词：
Age Aging Area Award Biology of Aging Biometry Cell Aging Cell Cycle Arrest Cell model Cells Cellular Morphology Cellular biology Chronic Chronic Obstructive Airway Disease Cigarette DNA Damage Data Development Development Plans Disease Down-Regulation Ensure Environment Epithelial Cells Exposure to Extracellular Matrix Family Fibroblasts Functional disorder Future Galactosidase Genes Genetic Genomic Instability Habits Hereditary Disease Human Impaired wound healing In Situ In Vitro Investigation Link Lung Lung diseases Mediating Mentors Modality Modeling Molecular Mutation Pathogenesis Pathway interactions Patients Phenotype Physicians Plasmids Premature aging syndrome Proteins Publishing Pulmonary Emphysema Regulation Research Research Design Research Personnel Retinoblastoma Protein Role Scientist Smoke Smoker Structure of parenchyma of lung TP53 gene Training Transfection Werner Syndrome Wound Healing abstracting career development cell motility cigarette smoke-induced cigarette smoking cigarette smoking helicase human WRN protein in vitro Model loss of function mutation lung injury meetings member migration multidisciplinary novel overexpression premature protein expression response senescence small hairpin RNA success

项目摘要

DESCRIPTION (provided by applicant): This application is to support the development of Dr. Toru Nyunoya into an independent researcher and an accomplished physician-scientist. Dr. Gary Hunninghake will support him as primary mentor to ensure the success of his career development plan. Specific areas of career development during this award include coursework, including cell biology, genetics, and biostatistics. The focus of this application is the investigation of mechanisms of cigarette smoke-induced fibroblast senescence. These studies directly relate to the pathogenesis of chronic obstructive pulmonary disease (COPD), which has been linked to cellular senescence, accelerated aging and impaired wound repair. Werner's syndrome (WS), a genetic disorder caused by loss-of-function mutations in the Werner's syndrome gene encoding a member of RecQ helicase family (WRN protein) also accelerates aging. However, to date, no study has explored the potential link between cigarette smoke-induced accelerated aging and WS. The candidate hypothesis is that exposure to cigarette smoke induces fibroblast senescence via WRN protein downregulation. In Aim 1, Dr. Nyunoya will identify the molecular pathway(s) responsible for cigarette smoke-induced cellular senescence in lung fibroblasts and in circulating fibrocytes from patients with COPD. Cigarette smoke-induced alterations in WRN protein expression will be examined in these different human models. To counter the cigarette smoke effect, WRN protein will be overexpressed using WRN plasmid transfection in cultured fibroblasts. A potential link between WRN protein and known senescence-inducing pathways such as p53 and p16 will be explored by knockdown using short hairpin RNA. In Aim 2, Dr. Nyunoya will determine the role of cigarette smoke-induced cellular senescence in an in vitro model of wound healing. Specifically, the role of p53, p16 and WRN protein in cigarette smoke-induced migration dysfunction and extracellular matrix regulation will be determined by shRNA knockdown of p53 and p16 or overexpression of WRN protein. Throughout Dr. Nyunoya's career development, he will meet with advisors in cell biology, aging, biostatistics and study design. This multidisciplinary training environment will enhance his career development and ensure that he evolves into an independent researcher. Elucidating the mechanisms of cigarette smoke-induced fibroblast senescence will contribute to our understanding of COPD pathogenesis and generate direction for future treatment modalities. (End of Abstract)

描述（由申请人提供）：