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: 9884784
• 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/9884784
• 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; Epithelial Cells; Epithelium; Event; Generations; Health; Immunocompromised Host; Impairment; Infection; Inhalation Therapy; Intervention; Investigation; Leukocytes; Lung; Mediator of activation protein; Mucous Membrane; Mus; Outcome; Patients; Pattern recognition receptor; Pneumonia; Population; Production; Public Health; Reactive Oxygen Species; Resistance; Scientific Advances and Accomplishments; Signal Transduction; Specific qualifier value; Surface; Survivors; Technology; Therapeutic; Time; Training; Translating; Translations; Vulnerable Populations; antimicrobial; antimicrobial peptide; design; 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.

项目摘要提取 肺炎每年导致数百万的死亡，并在许多幸存者中引起慢性健康复杂性 尽管巨大的表面积不断暴露于外部环境，但肺部的intrinsic 在建立感染之前，大多数病原体都可以 使用非直觉，协同合成的NOHAND疗法进行治疗刺激 模式识别受体激动剂组合。 病原体杀死并防止小鼠死亡，其他方向致消化的致命性肺炎，由双臂，病毒或病毒或病毒或 真菌病原体。 肺泡细胞是白细胞依赖性免疫促进疾病的患者。 提案支持一项计划，该计划调查了Thenomenon保护急性的机制 肺炎和慢性肺肺病，使对天然粘膜防御的了解更多 人口最有可能受益的人口，并促进对反对更有效的干预措施的发展 肺炎。 环境，而不是针对 Seriy Pursey可测试的元素假设迭代基于生成的数据。 企业1剖析了驱动肺炎保护的协同信号的机制，以启发如何 优化的一致检测检测可以通过新型传感器和放大器最大化保护信号。 企业2追求可诱导的活性氧范围生产的机制，以解释如何感应 和信号事件促进了由多重抗菌挥发性物种产生的协调。 企业3解决了实现广泛病原体杀戮的效应机制，以更好地定义 保护和研究抗菌肽和活性氧的未开发相互作用。 企业4探讨了促进持久不统一的e的机制，以确定 诱导性耐药性如何在延长的时间尺度上发挥EXTHMA和IMUNOPALOGY。 这些努力将批判信号事件和诱导电阻的效应器机制，揭示 意外的传感器相互作用，有助于发现更多更多的抗性诱导剂，并加快 该技术向诊所的翻译以保护患者的高峰脆弱性。