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

项目总结 对平民构成健康威胁的剧毒化学品的数量和种类如下 范围很广。国土安全部已确定近200家HTC为可信的公共卫生和 安全威胁。HTCs包含不同的化学类别和毒性机制，包括酸、烷基化 药物、发泡剂、代谢毒药、细胞呼吸抑制药，以及许多毒性研究不足的药物 和机械装置。然而，只有一小部分已知的HTC得到了很好的表征，并且仍然存在 迫切需要提高我们对启动过程中涉及的生理机制的理解 而暴露后的下游伤害事件对HTCS的研究不足。 与这一提议相关的是，我们已经开发出微生理3D人体呼吸道器官组织等效物 (OTE)平台，用于模拟氯气暴露引起的肺毒性并识别 新的伤害机制和测试潜在的医学对策(MCM)。我们的HTC曝光率 系统允许安全地将广泛的气体、蒸汽或雾化液体HTCs输送到肺OTES 精确度和准确度。我们已经建立了快速确定剂量/毒性关系的分析方法， 与生理相关的化学、生物和功能毒性机制和功能评估 转录分析用于发现新的毒性途径和MCM靶点。我们的总体假设是 我们已建立的航空OTE-HTC传递系统和转录生物信息学能力可以 应用于不同类别的HTCs，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，这项提议有望提高我们对 急性暴露于大量未被研究的HTCs造成的伤害。快速确定剂量/毒性关系 而未被研究的HTCs的作用机制将对理解以下潜在风险产生重大影响 大规模HTC暴露事件。最后，确定常见的分子损伤反应途径的可能性 一系列HTC类型可能会对识别和部署有效的医疗 广泛应用于未确定的或未被研究的高技术转换的对策。未来的工作将会加快 MCM的发现、再利用和发展，具有更广泛的适用于肺部威胁的范围。

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.