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: 10559552
• 负责人: Stefanie Krick
• 金额: $ 45.3万
• 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/10559552
• 关键词: Abate; Acceleration; 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; Economic Burden; 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 Factor beta; Transforming Growth Factors; airway inflammation; airway obstruction; anti aging; bronchial epithelium; comorbidity; cystic fibrosis airway; cystic fibrosis patients; cytokine; experience; functional improvement; health economics; improved; in vivo; in vivo Model; inhibitor; interdisciplinary approach; interest; liver inflammation; lung injury; mortality; muco-obstructive airway diseases; mucoid; mucus clearance; mucus-associated lung diseases; 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.

项目总结