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

Award Number: R01ES034416
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/25/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $310,000 )
2025	2025	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Environmental Health	000	3	8/13/2025	NON-COMPETING CONTINUATION	$310,000
														Subtotal = $310,000

Issue Date FY: 2024 ( Subtotal = $310,000 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Environmental Health	000	2	8/7/2024	NON-COMPETING CONTINUATION	$310,000
														Subtotal = $310,000

Issue Date FY: 2023 ( Subtotal = $310,000 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Environmental Health	000	1	8/24/2023	NEW	$310,000
														Subtotal = $310,000

Grand Total All Awards = $930,000

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

Award Number: R01ES034416

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/25/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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