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

摘要 该项目的长期目标是确定成纤维细胞生长因子23和klotho是潜在的衰老 COPD亚组的标记物，并开发针对这些途径的未来治疗策略。 慢性阻塞性肺疾病(COPD)目前是#年导致死亡的第三大原因 北美和大多数病例都是由香烟烟雾引起的。临床和细胞证据 支持加速肺老化是其发病的潜在机制的观点。 我们有很好的体外模型和体内模型来分析FGF23和Klotho之间的串扰以及他们的 对呼吸道上皮细胞衰老的影响。此外，我们将利用COPDgene队列来 翻译这些发现，以确定它们与慢性阻塞性肺疾病患者的相关性。 FGF23和Klotho都与慢性呼吸道炎症和加速衰老有关 COPD和我们的假设是Klotho/FGF23调节失调的变阻器参与了呼吸道上皮细胞 衰老。因此，我们建议研究潜在的分子机制，以确定 未来新的治疗靶点。 目的1研究FGF23信号增强对原代培养的大鼠呼吸道上皮细胞衰老的影响。 人呼吸道上皮细胞培养和小鼠，Klotho缺乏或过度表达Klotho，并将其暴露于 香烟烟雾？FGF23。 AIM 2将确定慢性支气管炎患者加速呼吸道老化的潜在分子机制 并将Klotho和FGF23表征为预测衰老的标记物 获取血浆样本和未确认的临床数据。 总之，这项提议将确定一条参与呼吸道上皮细胞衰老的新途径，从而导致 吸烟引起的肺部疾病，如慢性阻塞性肺病，因此为以下疾病开辟了新的治疗选择 由于人口老龄化，这一数字呈上升趋势。

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.