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Fibroblast Growth Factor 23/Klotho Crosstalk and Airway Epithelial Senescence in COPD

成纤维细胞生长因子 23/Klotho 串扰与 COPD 中的气道上皮衰老

基本信息

批准号：
9751171
负责人：
Stefanie Krick
金额：
$ 11.14万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751171
关键词：
Affinity Age Aging Air Ancillary Study Arteriosclerosis Atrophic condition of skin Cell Aging Cell Culture Techniques Chronic Chronic Kidney Failure Chronic Obstructive Airway Disease Clinical Clinical Data Complement Data Development Plans Disease Disease Progression Enrollment Environmental Pollutants Epithelial Epithelial Cells Exhibits Exposure to FGFR1 gene FGFR4 gene Fibroblast Growth Factor Receptor 1 Fibroblast Growth Factor Receptors Funding Future Goals Heart Hypertrophy Hormones Human In Vitro Individual Infertility Inflammation Inflammatory Life Expectancy Link Liquid substance Longevity Lung Lung diseases Measures Mentors Mitogen-Activated Protein Kinases Modeling Molecular Mus North America Osteoporosis Pathogenesis Pathway interactions Patients Phospholipase Physicians Plasma Positioning Attribute Predictive Value Premature aging syndrome Prospective cohort Proteins Pulmonary Emphysema Pulmonary Function Test/Forced Expiratory Volume 1 Radiology Specialty Recombinants Research Respiratory physiology Sampling Scientist Severity of illness Signal Pathway Signal Transduction Smoke Supplementation Therapeutic Training Translating Translational Research Visit Vital capacity aging population airway epithelium airway inflammation anti aging career development cell injury cell type cigarette smoke cigarette smoke-induced circulating biomarkers cohort disorder subtype fibroblast growth factor 23 follow-up in vitro Model in vivo in vivo Model inhibitor/antagonist mortality multidisciplinary new therapeutic target non-smoker novel novel therapeutic intervention novel therapeutics overexpression phospholipase C gamma prognostic senescence skills smoke-induced lung disease tool translational approach

项目摘要

ABSTRACT The long-term goal of this project is to identify Fibroblast Growth Factor (FGF) 23 and klotho as potential aging markers in COPD subgroups and develop future therapeutic strategies targeting these pathways. Chronic obstructive pulmonary disease (COPD) currently represents the third leading cause of mortality in North America and the majority of cases are caused by cigarette smoke. Both clinical and cellular evidence support the concept that accelerated lung aging serves as an underlying mechanism for its pathogenesis. We have good in vitro models and in vivo models to analyze the crosstalk between FGF23 and klotho and their effect on cell senescence in the airway epithelium. In addition, we will employ the COPDGene cohort to translate these findings to determine their relevance in individuals with COPD. Both FGF23 and klotho have been associated with chronic airway inflammation and accelerated aging in COPD and we hypothesize that a dysregulated klotho/FGF23 ‘rheostat’ contributes to airway epithelial cell senescence. We therefore propose to investigate the underlying molecular mechanisms in order to identify future novel therapeutic targets. Aim 1 will investigate the impact of increased FGF23 signaling on airway epithelial cell senescence by primary human airway epithelial cell cultures and mice, deficient in klotho or overexpressing klotho and expose them to cigarette smoke ± FGF23. Aim 2 will determine the underlying molecular mechanisms on accelerated airway aging in individuals with COPD and characterize klotho and FGF23 as prognostic aging markers by using the COPDGene cohort with access to plasma samples and de-identified clinical data. Overall, this proposal will identify a novel pathway involved in airway epithelial cell senescence leading to smoke induced lung diseases such as COPD and therefore open novel therapeutic options in diseases that are on the rise due to an aging population.

摘要