Characterizing chemical threat agent exposures using a lung-on-a-chip platform and multi-omic analysis of common pathophysiological mechanisms

使用芯片肺平台和常见病理生理机制的多组学分析来表征化学威胁剂暴露

• 批准号: 10708553
• 负责人: Sean Vincent Murphy
• 金额: $ 31万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-25 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708553
• 关键词: 3-Dimensional; Acceleration; Acids; Acute; African American population; Alkylating Agents; Area; Authorization documentation; Biochemical; Bioinformatics; Biological; Biological Assay; Bulla; Caucasians; Cell Respiration; Cells; Chemical Exposure; Chemical Weapons; Chemically Induced Toxicity; Chemicals; Cilia; Country; Databases; Development; Docking; Dose; Ethnic Origin; Evaluation; Event; Exposure to; FDA approved; Female; Frequencies; Funding; Future; Gases; Genes; Health; Hispanic Populations; Hour; Human; In Vitro; Industrialization; Inflammatory; Injury; Intervention; Lethal Dose 50; Liquid substance; Lung; Measures; Mediator; Military Personnel; Modeling; Molecular; Molecular Target; Nebulizer; Nuclear; Ontology; Organ; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Pesticides; Physiological; Poison; Population; Probability; Procedures; Public Health; Radiology Specialty; Risk; Safety; Security; Signal Transduction; Surface; System; Testing; Tissues; Toxic effect; Toxicokinetics; Validation; Vesicants; Work; authority; bioinformatics pipeline; chemical threat; chlorine gas; differential expression; improved; in silico; inhibitor; innovation; lung injury; male; manufacturing scale-up; mass casualty; medical countermeasure; metabolic poison; multiple omics; novel; programs; racial diversity; rapid test; research and development; response; transcriptome; transcriptomics; vapor

PROJECT SUMMARY The number and variety of Highly Toxic Chemicals (HTCs) that pose a health risk to the civilian population is extensive. The Department of Homeland Security has identified close to 200 HTCs as credible public health and safety threats. HTCs comprise diverse chemical classes and toxicity mechanisms including acids, alkylating agents, vesicating agents, metabolic poisons, cellular respiration inhibitors, and many with understudied toxicity and mechanisms. However only a small subset of known HTCs have been well-characterized, and there remains an urgent unmet need to improve our understanding of the physiological mechanisms involved in the initiation and downstream events of injury following exposure understudied HTCs. Relevant to this proposal, we have developed micro-physiological 3D human airway Organ Tissue Equivalent (OTE) platform for modeling pulmonary toxicity resulting from exposure to chlorine gas and for identification of novel mechanisms of injury and for testing of potential medical countermeasures (MCMs). Our HTC exposure system allows safe delivery of a broad range of gas, vapor or nebulized liquid HTCs to lung OTEs with high precision and accuracy. We have established assays rapidly determining dose/toxicity relationships, physiologically relevant chemical, biological and functional evaluation of mechanisms of toxicity and transcriptomic analysis for the discovery of novel toxicity pathways and MCM targets. Our overall hypothesis is that our established airway OTE - HTC delivery system and transcriptomic bioinformatic capabilities can be applied to different classes of HTCs to characterize mechanisms of toxicity and define potential molecular targets for MCM intervention. If successful, this proposal promises to improve our understanding of the initiation and downstream events of injury on acute exposure of a broad range of understudied HTCs. Rapidly defining dose/toxicity relationships and mechanisms of action of understudied HTCs will have a major impact on understanding potential risks for mass HTC exposure events. Finally, the potential to identify common molecular pathways of injury in response to a range of HTC types could have a significant impact in identifying and deploying effective medical countermeasures with broad application across unidentified or understudied HTCs. Future work will accelerate MCM discovery, repurposing and development with broader applicability across the pulmonary threat spectrum.

项目摘要 对平民构成健康风险的剧毒化学物质（HTC）的数量和种类是 广泛的。国土安全部已将近200个HTC确定为可靠的公共卫生，并且 安全威胁。 HTC包括各种化学类别和毒性机制，包括酸，烷基化 剂，囊泡剂，代谢毒物，细胞呼吸抑制剂以及许多研究毒性 和机制。但是，只有一小部分已知的HTC已被充分表征，并且仍然存在 紧迫的未满足需要，以提高我们对启动中涉及的生理机制的理解 暴露于HTC后，受伤的下游事件。 与该建议相关，我们开发了微观生理3D人体气道器官组织 （OTE）建模暴露于氯气和鉴定的肺毒性的平台 损伤的新型机制和潜在医疗对策（MCMS）的测试。我们的HTC暴露 系统允许安全地输送大量的气体，蒸气或雾化液体HTC，以高于肺 精度和准确性。我们已经建立了迅速确定剂量/毒性关系的测定法， 生理上相关的化学，生物学和功能评估毒性机制和 转录组分析，用于发现新型毒性途径和MCM靶标。我们的总体假设是 我们已建立的气道OTE -HTC输送系统和转录组生物信息学的能力可以是 应用于不同类别的HTC，以表征毒性机制并定义潜在的分子靶标 用于MCM干预。 如果成功，该提案有望提高我们对 大量研究的HTC急性暴露时受伤。快速定义剂量/毒性关系 研究不足的HTC的作用机制将对理解潜在风险的潜在风险产生重大影响 大规模HTC暴露事件。最后，识别损伤的常见分子途径的潜力 对于一系列HTC类型，可能会对识别和部署有效的医学产生重大影响 在身份不明或研究的HTC中与广泛应用的对策。未来的工作将加速 MCM发现，重新利用和开发，在整个肺威胁范围内具有更广泛的适用性。