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

靶向成纤维细胞生长因子受体治疗囊性纤维化相关气道炎症和粘液纤毛功能障碍

• 批准号: 10339681
• 负责人: Stefanie Krick
• 金额: $ 41.59万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339681
• 关键词: Abate; Address; Adult; Aging; Air; Animal Model; Anti-Inflammatory Agents; Atherosclerosis; Attenuated; Bacterial Infections; Caring; Cell Culture Techniques; Cell physiology; Chronic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Disease; Endocrine; Epithelial Cells; Exhibits; FGFR1 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Functional disorder; Genes; Genotype; Health; Human; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Innate Immune Response; Laboratories; Life; Life Expectancy; Ligands; Link; Liquid substance; Lung; Lung diseases; Mission; Modeling; Morbidity - disease rate; Mucociliary Clearance; Multiple Bacterial Drug Resistance; Mutation; National Heart, Lung, and Blood Institute; Obstruction; Organ; Population; Predisposition; Prevention; Protein Isoforms; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Public Health; Publishing; Pulmonary Cystic Fibrosis; Pulmonary Fibrosis; Pulmonary Inflammation; Quality of life; Rattus; Receptor Inhibition; Receptor Signaling; Recurrence; Research; Respiratory Tract Infections; Risk; Role; Sepsis; Serum; Severities; Signal Pathway; Signal Transduction; Structure; Structure of parenchyma of lung; Supplementation; Testing; Therapeutic Intervention; Transforming Growth Factors; airway inflammation; airway obstruction; anti aging; base; bronchial epithelium; comorbidity; cystic fibrosis airway; cystic fibrosis patients; cytokine; experience; functional outcomes; improved; in vivo; in vivo Model; inhibitor; interdisciplinary approach; interest; liver inflammation; lung injury; mortality; mucoid; mucus clearance; novel; novel therapeutic intervention; overexpression; pathogen; pulmonary function; pulmonary function decline; receptor; receptor expression; recurrent infection; socioeconomics; therapeutic target

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.

项目摘要 囊性纤维化（CF）是最常见的寿命单基因有缺陷的疾病，超过70,000 全球案件。在过去的几十年中，CF患者的死亡率显着下降，我们正面临 CF人群的新待遇挑战。而CF跨膜电导调节器（CFTR） 调节剂治疗对许多CF表现有效，气道炎症是CF肺部病的标志 不会持续影响导致粘液清除受损和对慢性气道感染的敏感性。 因此，确定改善CF相关慢性的新型治疗方法是非常有趣的 炎症，粘膜功效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（FGF）信号传导，这是一种表征良好的促炎性 在CF肺病中激活了衰老信号通路。我们假设FGF受体（FGFR） 抑制作用会减弱与CF相关的炎症和粘膜毛的间隙受损。我们将测试我们的 假设通过采用多学科方法将细胞培养与动物模型相结合，包括 慢性气道感染模型。 AIM 1将在体外建立FGFR抑制对气道炎症和粘膜纤毛清除的影响 使用原代人支气管上皮细胞的人类CF肺，从不同的空气液体界面培养 CF基因型。体内AIM 2将在既定的CF大鼠模型中概括这些发现并评估 FGFR抑制作用及其对CF相关炎症，粘液刺激性疾病和肺功能的影响。 AIM 3将进一步在体内慢性感染的CF肺中建立FGFR调节。 该提案的总体目的是确定FGFR调制在CF相关肺中的作用 并发症是一种可正常的治疗靶点，以最终改善功能结果，生活质量， 在不断增长的CF患者人群中的长期生存。