Innate Immune Defect and Neutrophilic Inflammation in Cystic Fibrosis

囊性纤维化中的先天免疫缺陷和中性粒细胞炎症

基本信息

批准号：
10470027
负责人：
GUOSHUN WANG
金额：
$ 36.84万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470027
关键词：
Abnormal Neutrophil Address Affect Agonist Apoptosis Arachidonic Acids Attention Bacteria Bacterial Infections Blocking Antibodies Bone Marrow Transplantation Cell Death Cells Cessation of life Characteristics Chemicals Chemotactic Factors Chloride Channels Chronic Chronic Disease Clinical Complement 5a Complement Activation Complication Cyclic AMP Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator DNA Sequence Alteration Data Defect Development Disease Epithelial Epithelial Cells FDA approved Genes Genetic Diseases Human Immune Infiltration Inflammation Inflammatory Inflammatory Response Inhalation Interleukin-8 Intravenous Irrigation Knock-out Knockout Mice Knowledge Label Leukotriene B4 Link Liquid Chromatography Liquid substance Live Birth Lung Marrow Microbe Modification Molecular Morbidity - disease rate Mutation Myelogenous Necrosis Organ Outcomes Research Oxidants Pathogenesis Pathologic Pathology Pathway interactions Patients Phagocytes Pharmaceutical Preparations Pharmacologic Substance Play Production Pseudomonas aeruginosa Pulmonary Challenge Pulmonary Cystic Fibrosis Pulmonary Inflammation Pulmonary Pathology Regulator Genes Research Role Source Structure Testing Time Tissues Tracer United States Wild Type Mouse Zymosan airway obstruction antagonist beta-Glucans body system cell type chemokine cystic fibrosis airway epithelia cystic fibrosis mouse cystic fibrosis patients cytokine effective intervention effective therapy extracellular formyl peptide gene therapy insight loss of function macrophage monocyte mortality neutrophil new therapeutic target novel rational design receptor recruit tandem mass spectrometry therapeutically effective

项目摘要

ABSTRACT Cystic fibrosis (CF) is one of the most common and deadly genetic disorders, affecting ~1/3,000 live births in the United States. The responsible genetic mutations are linked to the gene that encodes CF Transmembrane-conductance Regulator (CFTR), a cAMP-activated chloride channel. Although this disease affects almost all organs and systems, its lung complications claim the most morbidity and mortality. The prominent lung pathology is marked by chronic bacterial infection, persistent neutrophilic inflammation, and purulent small airway obstruction, of which persistent lung inflammation is responsible for lung structure damage and function loss. Even though the CF molecular defect was discovered three decades ago, the link between the CFTR chloride channel defect and the destructive lung inflammation has not been defined. Such a knowledge gap impedes any informed development of effective therapies for CF. The current proposal is to address this outstanding problem in the field. Our overarching hypothesis is that CFTR loss-of-function in marrow-derived innate immune cells compromises their ability to molecularly modify and functionally deactivate inflammatory agonists, leading to excessive stimulation and neutrophilic inflammation in CF lungs. To test this hypothesis, we propose three specific aims: Aim 1: Determine that lineage-specific CFTR loss-of-function in neutrophils and monocytes/macrophages leads to persistent neutrophilic inflammation in the lung differentially; Aim 2: Determine that CF lung neutrophilic inflammation is due to neutrophil excessive recruitment, reduced apoptosis, and/or inefficient efferocytosis; Aim 3: Define that CF neutrophils and macrophages are compromised in chemical modification and functional deactivation of neutrophil chemotactic factors. Completion of this research will provide novel insights into CF lung disease pathogenesis. The new knowledge obtained will guide the rational design of interventions for effective treatment of this devastating disease.

抽象的囊性纤维化（CF）是最常见和致命的遗传疾病之一，影响了约1/3,000个活产在美国。负责的基因突变与编码CF的基因有关跨膜传导调节剂（CFTR），一种营地活化的氯化物通道。虽然这种疾病影响几乎所有的器官和系统，其肺并发症声称最发病率和死亡率。这显着的肺病理学以慢性细菌感染，持续性嗜中性炎症和化脓性小气道阻塞，其中持续性肺部炎症是肺结构的原因损坏和功能损失。即使三十年前发现了CF分子缺陷，该链接在CFTR氯化物通道缺陷和破坏性肺部炎症之间尚未定义。这样的知识差距阻碍了CF的有效疗法的任何明智的发展。当前的建议是解决该领域的这个杰出问题。我们的总体假设是CFTR的功能丧失骨髓来源的先天免疫细胞损害了它们分子修饰并在功能上停用的能力炎症激动剂，导致CF肺中过度刺激和中性粒细胞炎症。测试这个假设，我们提出了三个具体目的：目标1：确定谱系特异性的CFTR功能丧失中性粒细胞和单核细胞/巨噬细胞导致肺部持续的嗜中性炎症。 AIM 2：确定CF肺嗜中性炎症是由于中性粒细胞过多的募集，减少了细胞凋亡和/或效率低下的胞吞作用； AIM 3：定义CF中性粒细胞和巨噬细胞是在中性粒细胞趋化因子的化学修饰和功能失活方面受到损害。这项研究的完成将为CF肺病发病机理提供新的见解。新知识获得的将指导干预措施的合理设计，以有效治疗这种毁灭性疾病。