Inducible epithelial resistance: a program investigating mechanisms to protect against acute and chronic complications of pneumonia

诱导上皮抵抗：一项研究预防肺炎急性和慢性并发症机制的计划

• 批准号: 10614561
• 负责人: Scott E. Evans
• 金额: $ 88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-05 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614561
• 关键词: Acute; Acute Pneumonia; Address; Agonist; Alveolar Cell; Amplifiers; Area; Asthma; Cessation of life; Chronic; Chronic lung disease; Clinic; Data; Detection; Development; Environment; Epithelial Cells; Epithelium; Event; Generations; Health; Immunocompromised Host; Impairment; Infection; Inhalation Therapy; Investigation; Leukocytes; Lung; Mediator; Mucous Membrane; Mus; Outcome; Patients; Pattern recognition receptor; Pneumonia; Population; Predisposition; Production; Public Health; Reactive Oxygen Species; Resistance; Scientific Advances and Accomplishments; Signal Transduction; Source; Specific qualifier value; Surface; Survivors; Technology; Therapeutic; Time; Training; Translating; Translations; Volatilization; Vulnerable Populations; antimicrobial; antimicrobial peptide; design; efficacious intervention; immunopathology; immunoregulation; novel; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; prevent; programs; response; sensor

PROJECT SUMMARY-ABSTRACT Pneumonias cause millions of deaths annually and cause chronic health complications in many survivors. Yet, despite constant exposure of an immense surface area to the external environment, the lungs’ intrinsic defenses clear most pathogens before infections are established. These mucosal defenses can be therapeutically stimulated using a novel inhaled therapy comprised of a non-intuitive, synergistic synthetic pattern recognition receptor agonist combination. This inducible resistance results in rapid intrapulmonary pathogen killing and prevents death in mice from otherwise lethal pneumonias caused by bacterial, viral or fungal pathogens. Lung epithelial cells are principal mediators of this response, and reliance on airway and alveolar cells is fortuitous for patients with leukocyte-dependent immunocompromising conditions. The current proposal supports a program investigating the mechanisms by which this phenomenon protects against acute pneumonia and chronic lung disease, allowing greater understanding of native mucosal defenses, identifying populations most likely to benefit, and promoting development of more efficacious interventions against pneumonia. This program is designed to produce the greatest scientific advance and most robust training environment, so rather than targeting pre-specified milestones, investigations align within four self-sustaining enterprises that serially pursue testable hypotheses then iteratively build upon the generated data. Enterprise 1 dissects the mechanisms of synergistic signaling that drive pneumonia protection to reveal how optimized coincident detection can maximize the protective signal through novel sensors and amplifiers. Enterprise 2 pursues the mechanisms of inducible reactive oxygen species production to explain how sensing and signaling events promote coordinated generation of multisource antimicrobial volatile species. Enterprise 3 addresses the effector mechanisms that achieve broad pathogen killing to better define the extent of protection and investigate unexplored interactions of antimicrobial peptides and reactive oxygen species. Enterprise 4 explores the mechanisms that promote durably induced immunomodulatory effects to determine how inducible resistance exerts effects against asthma and immunopathology over extended time scales. These efforts will identify critical signaling events and effector mechanisms of inducible resistance, reveal unanticipated sensor interactions, facilitate discovery of more efficacious inducers of resistance, and expedite the translation of this technology into the clinic to protect patients during periods of peak vulnerability.

项目概要-摘要 肺炎每年导致数百万人死亡，并导致许多幸存者出现慢性健康并发症。 尽管肺的表面积不断暴露在外部环境中，但其内在的 这些粘膜防御可以在感染建立之前清除大多数病原体。 使用由非直观的协同合成物组成的新型吸入疗法进行治疗刺激 模式识别受体激动剂组合导致快速肺内耐药。 杀死病原体并防止小鼠因细菌、病毒或细菌引起的致命性肺炎而死亡 真菌病原体是这种反应的主要介质，并且依赖于气道和 对于患有白细胞依赖性免疫功能低下疾病的患者来说，肺泡细胞是偶然的。 提案支持一项计划，调查这种现象防止急性发作的机制 肺炎和慢性肺部疾病，可以更好地了解天然粘膜防御，识别 最有可能受益的人群，并促进制定更有效的干预措施 该计划旨在产生最大的科学进步和最有力的培训。 环境，因此调查不是针对预先指定的里程碑，而是在四个自我维持的范围内进行协调 企业连续追求可检验的假设，然后迭代地基于生成的数据进行构建。 Enterprise 1 剖析了推动肺炎保护的协同信号传导机制，以揭示如何 优化的重合检测可以通过新颖的传感器和放大器最大化保护信号。 Enterprise 2 探究诱导型活性氧产生的机制，以解释传感如何 和信号事件促进多源抗菌挥发性物质的协调产生。 Enterprise 3 解决了实现广泛病原体杀灭的效应机制，以更好地定义杀灭程度 保护并研究抗菌肽和活性氧的未探索的相互作用。 Enterprise 4 探索促进持久诱导的免疫调节作用的机制，以确定 诱导抵抗如何在较长时间内对哮喘和免疫病理学产生影响。 这些将识别诱导抗性的关键信号事件和效应机制，揭示 意想不到的传感器相互作用，促进发现更有效的耐药诱导剂，并加快 将这项技术转化为临床，以在最脆弱时期保护患者。