Targeting fibroblast growth factor receptors in cystic fibrosis-associated airway inflammation and mucociliary dysfunction

项目摘要 囊性纤维化是最常见的致命性单基因缺陷性疾病之一，约有70,000例 世界各地的病例。在过去的几十年里，CF患者的死亡率显著下降，我们面临着 面对老龄化的CF人群的新的治疗挑战。而CF跨膜电导调节器(CFTR) 调节剂治疗对许多CF表现有效，呼吸道炎症是CF肺部疾病的一个标志 不会持续受到影响，导致粘液清除受损，并易患慢性呼吸道感染。 因此，寻找新的治疗方法来改善慢性循环衰竭是非常有意义的。 炎症、粘液纤毛功能障碍和反复感染最终适用于所有CF患者。我们 最近发表了成纤维细胞生长因子(成纤维细胞生长因子)信号转导，一个很好的特点是促炎 而衰老信号通路在慢性肺病中被激活。我们假设成纤维细胞生长因子受体(FGFR) 抑制作用将减轻CF相关的炎症和受损的粘液纤毛清除。我们将测试我们的 通过使用多学科方法结合细胞培养和动物模型进行假说，包括 慢性呼吸道感染模型。 目的1建立体外抑制FGFR对大鼠气道炎症和粘液纤毛清除的影响。 利用原代人支气管上皮细胞，在气液界面上培养不同来源的人肺纤维细胞 Cf基因分型。体内AIM 2将在已建立的CF大鼠模型中总结这些发现并评估 FGFR抑制及其对CF相关性炎症、粘膜阻塞性疾病和肺功能的影响。 目的3进一步在慢性感染肺组织中建立FGFR的体内调控机制。 这项建议的总体目标是确定FGFR在CF相关肺中的调节作用 并发症作为一个顺从的治疗目标，最终改善功能结果，生活质量， 以及在日益增长的老年CF患者群体中的长期存活率。

Project Summary Cystic fibrosis (CF) is one the most common life-shortening single gene defective disorders with over 70,000 cases worldwide. Mortality of CF patients has significantly decreased over the last decades and we are facing new treatment challenges for an aging CF population. While CF transmembrane conductance regulator (CFTR) modulator therapy is effective for many CF manifestations, airway inflammation as a hallmark of CF lung disease is not consistently impacted leading to impaired mucus clearance and susceptibility to chronic airway infections. Therefore, it is of great interest to identify novel therapeutic approaches that improve CF-associated chronic inflammation, mucociliary dysfunction and recurrent infections to be ultimately applicable for all CF patients. We have recently published that Fibroblast Growth Factor (FGF) signaling, a well characterized pro-inflammatory and aging signaling pathway, is activated in CF lung disease. We hypothesize that FGF receptor (FGFR) inhibition will attenuate CF-associated inflammation and impaired mucociliary clearance. We will test our hypothesis by employing a multidisciplinary approach combining cell culture with animal models including a chronic airway infection model. Aim 1 will establish the effects of FGFR inhibition in vitro on airway inflammation and mucociliary clearance in the human CF lung using primary human bronchial epithelial cells, cultured at the air liquid interface from different CF genotypes. The in vivo Aim 2 will recapitulate these findings in established CF rat models and assess FGFR inhibition and its impact on CF-associated inflammation, muco-obstructive disease and lung function. Aim 3 will further establish FGFR modulation in the chronically infected CF lung in vivo. The overall aim of this proposal is to establish the role of FGFR modulation in CF associated lung complications as an amenable therapeutic target to ultimately improve functional outcomes, quality of life, and long-term survival in the growing population of aging individuals with CF.