Rescue of CF phagocyte function with CFTR modulator therapy

项目总结 为什么囊性纤维化(CF)患者继续遭受慢性细菌感染 改善CF跨膜电导调节器(CFTR)功能的新药是 未知。这项建议的目标是定义新的三重组合如何非常有效 CFTR调节剂治疗(HEMT)改变了CF吞噬细胞的功能。背后的基本原理 这一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患者无法通过几种途径清除细菌感染是不可或缺的 功能失调的机制。这些机制中的许多只是部分服从于 使用目前可用的CFTR型调制器进行治疗。中心假设是CF 吞噬细胞功能依赖于功能性CFTR，可通过HEMT恢复，并且 与临床反应相关。核心假设将通过追求三个方面来检验 具体目标：1)确定HEMT是否改变了CF巨噬细胞的功能CFTR和 中性粒细胞；2)评估HEMT处理的巨噬细胞和中性粒细胞功能反应 感染；以及3)个体的临床反应与吞噬细胞功能相关。我们会 使用独特的模型和分析来追求这些目标，其中包括人巨噬细胞和 中性粒细胞及其与具有良好特征的临床数据的相关性。拟议的研究是 重要的是因为对CF巨噬细胞和中性粒细胞功能的精确了解 由HEMT监管，将允许采用新的、个性化的治疗方法来治疗CF感染 以及其他疾病。这项工作的预期结果将建立一个机制框架 使我们能够针对和纠正有缺陷的杀灭CF中的细菌。长期目标是 开发治疗方法，调节CF患者的宿主免疫反应，以缓解慢性 感染和炎症。最终，我们将把这种新知识转化为一种新的治疗方法 使用创新的宿主导向疗法来对抗细菌感染的范例。

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.