Resue of CF phagocyte function with CFTR modulator therapy

CFTR调节剂治疗对CF吞噬细胞功能的恢复

• 批准号: 10797778
• 负责人: Amal O Amer
• 金额: $ 53.17万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797778
• 关键词: 3-Dimensional; Affect; Antibiotic Therapy; Antibiotics; Autophagocytosis; Bacteria; Bacterial Infections; Biological Assay; Burkholderia cepacia; Cell physiology; Cells; Chronic; Clinical; Clinical Data; Communities; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Delta F508 mutation; Disease; Exposure to; Functional disorder; Generations; Genetic Diseases; Goals; Homeostasis; Human; Image Analysis; Immune; Immune response; Immune system; Immunologic Deficiency Syndromes; Impairment; Individual; Infection; Inflammation; Inflammatory; Ions; Knowledge; Life; Lung diseases; Lung infections; Macrophage; Mediating; Metadata; Microscopy; Mission; Mitochondria; Modeling; Mycobacterium abscessus; Outcome; Patients; Persons; Phagocytes; Pharmaceutical Preparations; Process; Production; Pseudomonas aeruginosa; Public Health; Reactive Oxygen Species; Research; Resolution; Resources; Signal Transduction; Staphylococcus aureus; Testing; Therapeutic; Translating; United States National Institutes of Health; VX-770; VX-809; Variant; Western Blotting; Work; antimicrobial; bacterial genetics; chronic infection; combat; cystic fibrosis infection; cystic fibrosis patients; extracellular; improved; innovation; insight; monocyte; neutrophil; non-tuberculosis mycobacteria; novel; nutrition; patch clamp; pathogen; personalized approach; personalized medicine; protein expression; pulmonary function; reconstruction; research clinical testing; respiratory; response; restoration; trafficking; treatment response; uptake

PROJECT SUMMARY Why patients with cystic fibrosis (CF) continue to suffer from chronic bacterial infections despite new medications that improve CF transmembrane conductance regulator (CFTR) function is unknown. The objective of this proposal is to define how new triple combination highly effective CFTR modulator therapy (HEMT) alters CF phagocytic cell function. The rationale underlying this proposal is that our prior work demonstrates that CF macrophages and neutrophils are integral to the inability of patients with CF to clear bacterial infections through several dysfunctional mechanisms. Many of these mechanisms are only partially amenable to treatment with currently available CFTR modulators. The central hypothesis is that CF phagocytic cell function is dependent on functional CFTR, can be restored by HEMT, and correlates with clinical responses. The central hypothesis will be tested by pursuing three specific aims: 1) Determine whether HEMT changes functional CFTR in CF macrophages and neutrophils; 2) Assess HEMT-treated macrophage and neutrophil functional responses to infection; and 3) Correlate individual clinical responses with phagocytic cell function. We will pursue these aims using unique models and assays that include human macrophages and neutrophils and association with well-characterized clinical data. The proposed research is significant because a precise understanding of how CF macrophage and neutrophil function is regulated by HEMT would allow novel, personalized treatment approaches to infection in CF and other diseases. The expected outcome of this work will establish a mechanistic framework to enable us to target and correct defective killing of bacteria in CF. The long-term goal is to develop therapeutics that modulate host immune responses in CF patients to mitigate chronic infection and inflammation. Ultimately, we will translate this new knowledge into a new treatment paradigm that uses innovative host-directed therapies to combat bacterial infections.

项目总结