Rescue of CF phagocyte function with CFTR modulator therapy

CFTR 调节剂治疗拯救 CF 吞噬细胞功能

• 批准号: 10445615
• 负责人: Amal O Amer
• 金额: $ 61.13万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 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 2022-08-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445615
• 关键词: 3-Dimensional; Address; 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; Equilibrium; 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; 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; macrophage; 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.

项目概要 为什么囊性纤维化 (CF) 患者尽管患有慢性细菌感染，但仍持续遭受慢性细菌感染 改善 CF 跨膜电导调节器 (CFTR) 功能的新药物是 未知。该提案的目的是定义新的三重组合如何高效 CFTR 调节剂疗法 (HEMT) 改变 CF 吞噬细胞功能。基本原理 这个建议是我们之前的工作表明CF巨噬细胞和中性粒细胞是 CF 患者无法通过多种方式清除细菌感染 机制失调。其中许多机制仅部分适用 使用目前可用的 CFTR 调节剂进行治疗。中心假设是 CF 吞噬细胞功能依赖于功能性CFTR，可以通过HEMT恢复，并且 与临床反应相关。中心假设将通过追求三个 具体目标： 1) 确定 HEMT 是否改变 CF 巨噬细胞中的功能性 CFTR，以及 中性粒细胞； 2) 评估 HEMT 处理的巨噬细胞和中性粒细胞的功能反应 感染; 3) 将个体临床反应与吞噬细胞功能相关联。我们将 使用独特的模型和检测来实现这些目标，其中包括人类巨噬细胞和 中性粒细胞以及与充分表征的临床数据的关联。拟议的研究是 意义重大，因为准确了解 CF 巨噬细胞和中性粒细胞的功能非常重要 HEMT 监管将为 CF 感染提供新颖、个性化的治疗方法 和其他疾病。这项工作的预期成果将建立一个机制框架 使我们能够瞄准并纠正 CF 中细菌的杀灭缺陷。长期目标是 开发调节 CF 患者宿主免疫反应的疗法，以减轻慢性 感染和炎症。最终，我们将把这些新知识转化为新的治疗方法 使用创新的宿主导向疗法来对抗细菌感染的范例。