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

项目摘要 对平民构成健康风险的剧毒化学品的数量和种类是 广泛。国土安全部已经确定了近200个HTC作为可信的公共卫生， 安全威胁。HTCs包括不同的化学类别和毒性机制，包括酸、烷基化 制剂、起泡剂、代谢毒物、细胞呼吸抑制剂，以及许多未充分研究的毒性 和机制。然而，只有一小部分已知的HTC已经得到了很好的表征， 一个迫切的未满足的需要，以提高我们的理解的生理机制参与启动 和下游事件的伤害暴露understudied HTCs。 与此相关，我们开发了微生理三维人体气道器官组织等效物 (OTE)用于模拟暴露于氯气导致的肺毒性和识别 新的损伤机制和测试潜在的医疗对策（MCMs）。HTC曝光 系统允许将广泛的气体、蒸汽或雾化液体HTC安全输送到肺OTE， 精确度和准确度。我们已经建立了快速确定剂量/毒性关系的测定方法， 毒性机制的生理相关化学、生物和功能评价， 转录组学分析用于发现新的毒性途径和MCM靶点。我们的总体假设是 我们建立的气道OTE-HTC输送系统和转录组生物信息学能力可以 应用于不同类别的HTC，以表征毒性机制并确定潜在的分子靶点 进行MCM干预。 如果成功的话，这一建议有望提高我们对太阳能电池的启动和下游事件的理解。 急性暴露于广泛的未充分研究的HTCs的损伤。快速确定剂量/毒性关系 研究不足的HTCs的作用机制将对理解潜在风险产生重大影响， 大量HTC曝光事件。最后，确定损伤的共同分子途径的潜力， 一系列的HTC类型可以在识别和部署有效的医疗 在未识别或未充分研究的HTC中广泛应用的对策。未来工作将加速推进 MCM的发现、再利用和开发，在肺部威胁范围内具有更广泛的适用性。

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.