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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：
10247817
负责人：
GUOSHUN WANG
金额：
$ 37.15万
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/10247817
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 Lung Inflammation 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 Cystic Fibrosis Pulmonary Fibrosis Pulmonary Pathology Regulator Genes Research Role Source Structure Testing Time Tissues Tracer United States Wild Type Mouse Zymosan airway obstruction beta-Glucans body system cell type chemokine cystic fibrosis airway epithelia cystic fibrosis mouse cystic fibrosis patients cytokine design effective therapy extracellular formyl peptide gene therapy insight loss of function macrophage monocyte mortality neutrophil new therapeutic target novel receptor recruit tandem mass spectrometry therapeutically effective therapy design

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.

摘要