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.

项目摘要 为什么囊性纤维化（CF）患者继续遭受慢性细菌感染，尽管 改善CF跨膜传导调节因子（CFTR）功能的新药物是 未知本提案的目的是确定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。所依据的理由 我们先前的工作表明CF巨噬细胞和中性粒细胞是 CF患者无法通过几种途径清除细菌感染的组成部分 功能失调的机制。这些机制中的许多只是部分地服从于 用目前可用的CFTR调节剂治疗。核心假设是CF 吞噬细胞功能依赖于功能性CFTR，可以通过HEMT恢复， 与临床反应相关。中心假设将通过追求三个测试 具体目的：1）确定HEMT是否改变CF巨噬细胞中的功能性CFTR， 2）评估HEMT处理的巨噬细胞和嗜中性粒细胞的功能反应， 感染;和3）将个体临床反应与吞噬细胞功能相关联。我们将 使用包括人类巨噬细胞在内的独特模型和测定来实现这些目标， 中性粒细胞和相关的良好表征的临床数据。拟议的研究是 因为精确了解CF巨噬细胞和中性粒细胞的功能 通过HEMT调节，将允许CF感染的新型个性化治疗方法 和其它疾病。这项工作的预期成果将建立一个机制框架， 使我们能够靶向和纠正CF中细菌的缺陷性杀灭。长期目标是 开发调节CF患者中的宿主免疫应答以减轻慢性炎症的治疗剂， 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 这是一个使用创新的宿主导向疗法来对抗细菌感染的范例。