The amyloid precursor protein protects against acute lung injury

淀粉样前体蛋白可预防急性肺损伤

• 批准号: 10575258
• 负责人: JONATHON PETER AUDIA
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575258
• 关键词: Acute; Acute Lung Injury; Adoptive Transfer; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Antibiotic Resistance; Bacterial Meningitis; Bacterial Pneumonia; Biological Assay; Biological Markers; Biological Process; Biology; Blood; Bone Marrow; Cell Culture Techniques; Cell physiology; Cerebrospinal Fluid; Chemotaxis; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Critical Illness; Cystic Fibrosis; Cytoplasmic Granules; Data; Diagnostic; ESKAPE pathogens; Etiology; Exhibits; Functional disorder; Future; Goals; Immune; In Vitro; Incidence; Infection; Infection Control; Inflammation; Inflammatory; Innate Immune Response; Intensive Care; Intensive Care Units; Invaded; Klebsiella pneumoniae; Knock-out; Knockout Mice; Left; Link; Lung; Lung infections; Measures; Mediating; Modeling; Molecular; Multiple Organ Failure; Mus; Natural Immunity; Neurobiology; Neurocognitive; Neuroglia; Neutrophil Activation; Neutrophil Infiltration; Organ; Organ failure; Pathology; Patients; Peripheral Blood Mononuclear Cell; Phagocytosis; Physiological; Plasma; Play; Pneumonia; Predisposition; Prevalence; Production; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Publishing; Quality of life; Recombinants; Recovery; Reporter; Respiratory Failure; Role; Sampling; Sepsis; Severities; Staphylococcus aureus; Survivors; Syndrome; Testing; Therapeutic; Tissues; Virulence Factors; Virus; Work; amyloid peptide; antimicrobial; antimicrobial peptide; biobank; cytokine; cytotoxic; drug resistant pathogen; experimental study; extracellular; fungus; improved outcome; innovation; long-term sequelae; lung injury; monocyte; mortality; neurotoxic; neutralizing antibody; neutrophil; novel; organ growth; outcome prediction; pathogen; pathogenic bacteria; pneumonia model; pneumonia treatment; protein expression; response; sepsis induced acute lung injury

PROJECT SUMMARY Neutrophil activation in response to infection is a double-edged sword that can either kill invading pathogens and/or inflict tissue damage. Thus, neutrophils inextricably define whether the innate immune response to infection is beneficial or deleterious to the host. The interdependence of neutrophil degranulation and release of extracellular traps (NETs) has emerged as an important player in acute and chronic inflammation. This new R21 proposal is based on the unexpected discovery that the amyloid precursor protein (APP) regulates neutrophil degranulation and NETosis during Pseudomonas aeruginosa infection in the lung. While APP is known to drive the pathology of Alzheimer's disease via production of neurotoxic β-amyloid peptides, a growing body of evidence highlights an interplay between APP, β-amyloid, and innate immunity. Mice lacking APP are more susceptible to bacterial meningitis, and β-amyloid is an antimicrobial peptide. Preliminary data are presented to support the premise that App knockout mice show increased mortality and lung injury compared to wild type controls in response to P. aeruginosa infection. Surprisingly, P. aeruginosa-infected App knockout mice also exhibit increased neutrophil influx compared to wild type controls. In addition, in vitro studies demonstrate that isolated bone marrow-derived neutrophils from App knockout mice display increased degranulation and NETosis. Together, these published and preliminary data support a conceptually innovative and technically feasible approach for two Specific Aims that will test the HYPOTHESIS that APP modulates neutrophil degranulation and NETosis to limit lung injury during P. aeruginosa infection. Aim 1 will elucidate the protective role of APP during P. aeruginosa-induced lung injury. Aim 2 will test the utility of APP and β-amyloid peptides as predictors of outcome in critically ill patients. Our discovery that APP protects the host during P. aeruginosa lung infection is a highly significant conceptual advance with broad impact across the fields of lung biology and neurobiology. P. aeruginosa is the most frequent Gram-negative pathogen causing pneumonia in patients with chronic lung disease (e.g., chronic obstructive pulmonary disease and cystic fibrosis), and is prevalent in critically ill patients with respiratory failure in the intensive care unit. In the most severe cases, pneumonia progresses to acute lung injury, sepsis, and multi-organ failure. Importantly, survivors often suffer long-term sequelae such as post-intensive care syndrome (PICS) and neurocognitive dysfunction that reduce overall quality of life. Thus, our proposed studies may reveal potentially transformative links between a pathogen-mediated dysfunctional APP response in neutrophils and organ dysfunction and neurocognitive sequelae.

项目概要 响应感染的中性粒细胞激活是一把双刃剑，可以杀死入侵的病原体 因此，中性粒细胞不可避免地决定了先天免疫反应是否会发生。 感染对宿主有益或有害 中性粒细胞脱颗粒和释放的相互依赖性。 细胞外陷阱（NET）已成为急性和慢性炎症的重要参与者。 该提案基于淀粉样前体蛋白（APP）调节的意外发现 肺部铜绿假单胞菌感染期间的中性粒细胞脱颗粒和 NETosis。 虽然已知 APP 通过产生神经毒性 β-淀粉样蛋白来驱动阿尔茨海默氏病的病理学 肽，越来越多的证据强调了 APP、β-淀粉样蛋白和小鼠先天免疫之间的相互作用。 缺乏APP的人更容易患细菌性脑膜炎，而β-淀粉样蛋白是一种初步的抗菌肽。 数据支持这样的前提：App 敲除小鼠死亡率和肺损伤增加 与野生型对照相比，铜绿假单胞菌感染的反应令人惊讶。 此外，与野生型对照相比，敲除小鼠还表现出中性粒细胞流入增加。 证明从 App 敲除小鼠中分离出的骨髓来源的中性粒细胞显示增加 这些已发表的初步数据共同支持了概念上的创新。 以及针对两个具体目标的技术上可行的方法，将测试 APP 调节的假设 目标 1 将通过中性粒细胞脱粒和 NETosis 来限制铜绿假单胞菌感染期间的肺损伤。 阐明 APP 在铜绿假单胞菌引起的肺损伤过程中的保护作用，目标 2 将测试 APP 的实用性。 和β-淀粉样肽作为危重患者预后的预测因子。 我们发现 APP 在铜绿假单胞菌肺部感染期间保护宿主，这是一个非常重要的发现 在肺生物学和神经生物学领域具有广泛影响的概念进步是铜绿假单胞菌。 慢性肺病（例如慢性肺病）患者中最常见的引起肺炎的革兰氏阴性病原体 阻塞性肺病和囊性纤维化），并且常见于患有呼吸衰竭的危重患者 在重症监护室中，最严重的情况下，肺炎会发展为急性肺损伤、败血症和 重要的是，幸存者经常遭受长期后遗症，例如重症监护后综合症。 （PICS）和神经认知功能障碍会降低整体生活质量因此，我们提出的研究可能会揭示。 中性粒细胞中病原体介导的功能失调 APP 反应与 器官功能障碍和神经认知后遗症。