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SUMMARY-ABSTRACT