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Targeting the endocannabinoid signaling in chemical threat agents-induced lung injury

Award Number: R56ES037610
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: 09/15/2025
PERIOD OF PERFORMANCE END DATE: 09/14/2026

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Targeting the endocannabinoid signaling in chemical threat agents-induced lung injury - Summary: The U.S. Department of Homeland Security (DHS) has identified over 200 chemicals of concern (CoCs) that threaten public health, with approximately 25% posing respiratory risks. Notably, nitrogen mustard (NM) and ammonia (NH3) are significant contributors to lung injury. Currently, there are no effective medical countermeasures to mitigate NM- or NH3-induced lung damage, therefore, the search for an effective therapeutic or prophylactic treatment persists. The endocannabinoids and their lipid-related mediators contribute to the modulation of oxidative stress and lipid peroxidation and 2- Arachidonoylglycerol (2-AG), is the most abundant endocannabinoid. 2-AG is produced ‘on demand’ and rapidly degraded, and monoacylglycerol lipase (MAGL or MgII) is the main enzyme responsible for 2-AG catabolism. The hydrolysis of 2-AG by MAGL terminates the activation of CB receptors, releasing free AA that serves as a precursor for the synthesis of pro-inflammatory eicosanoids. Enhancing the 2-AG signaling displays an anti-inflammatory response to proinflammatory and mechanical insults. Our preliminary findings indicate that acute exposure to NM or NH3 results in a significant increase in MAGL in mouse lung tissue. The NM-induced increase in MAGL was significantly higher in lung immune cells compared to alveolar epithelial and endothelial cells. A similar increase in MAGL was observed in human alveolar macrophages (HAMs) in response to NM exposure. Furthermore, our pilot study showed that the administration of JZL184, a potent and highly selective inhibitor of MAGL, resulted in a significant reduction in NM- and NH3-induced acute lung injury and immune cell infiltration in mice. Given these promising indications, this project aims to further investigate how augmenting the 2-AG signaling by inactivation of MAGL could confer protection against NM- or NH3-induced lung injury. Aim 1: To determine the extent to which MAGL inactivation/inhibition changes NM- or NH3-induced lung injury, inflammatory response, and toxicity. Aim 2: To determine the cellular and molecular responses of MAGL inactivation on NM or NH3-induced lung injury and inflammatory response. Aim 3: To delineate the mechanism by which MAGL inhibition/inactivation exerts the protective effects in NM or NH3-induced acute lung injury and inflammatory response.


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 = $489,008 )
2025	2025	OLD DOMINION UNIVERSITY	HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Environmental Health	000	1	9/15/2025	NEW	$489,008
														Subtotal = $489,008

Grand Total All Awards = $489,008

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Targeting the endocannabinoid signaling in chemical threat agents-induced lung injury

Award Number: R56ES037610

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: 09/15/2025

PERIOD OF PERFORMANCE END DATE: 09/14/2026

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