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

项目摘要 疟疾每年造成数百万人死亡，并在许多幸存者中造成慢性健康并发症。然而， 尽管肺的巨大表面积持续暴露于外部环境， 防御系统在感染建立之前清除了大多数病原体。这些粘膜防御可以是 使用由非直观的协同合成的化合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。这种可诱导的耐药性导致肺内快速 病原体杀灭，并防止小鼠死于细菌、病毒或 真菌病原体肺上皮细胞是这种反应的主要介质，并且依赖于气道和 肺泡细胞对于具有白细胞依赖性免疫损害病症的患者是偶然的。当前 一项提案支持一项研究这种现象保护急性 肺炎和慢性肺部疾病，从而更好地了解天然粘膜防御， 最有可能受益的人口，并促进制定更有效的干预措施， 肺炎该计划旨在产生最大的科学进步和最强大的培训 因此，调查不是针对预先规定的里程碑，而是在四个自我维持的 连续追求可测试假设的企业然后迭代地建立在所生成的数据上。 企业1剖析了驱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使保护信号最大化。 企业2追求诱导活性氧产生的机制，以解释如何感知 和信号传导事件促进多个抗微生物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器机制，以更好地定义 保护和研究未开发的抗菌肽和活性氧的相互作用。 企业4探索促进持久诱导的免疫调节作用的机制，以确定 诱导性抵抗如何在延长的时间尺度上对哮喘和免疫病理学发挥作用。 这些努力将确定诱导抗性的关键信号事件和效应机制，揭示 非预期的传感器相互作用，促进发现更有效的抗性诱导剂，并加速 将这项技术应用于临床，以在最脆弱的时期保护患者。

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.