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Inflammation and white matter microstructural alterations after OP exposure

Award Number: R21NS136126
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Inflammation and white matter microstructural alterations after OP exposure - Project Summary Exposure to organophosphate (OP) compounds such as diisopropylfluorophosphate (DFP) results in irreversible inhibition of acetylcholinesterase (AChE), excessive accumulation of acetylcholine within synapses, and overactivation of muscarinic and nicotinic acetylcholine receptors in the peripheral and central nervous system, leading to death. Civilian populations are at risk from OP exposure. Toxic signs (hypersecretions, vomiting, diarrhea, tremors, status epilepticus [SE], respiratory distress, death) can ensue within minutes of exposure. Current medical countermeasures are effective acutely but may not prevent long-term consequences. It is known that OP compounds cause white matter damage in monkeys. In humans, white matter volume reduction is observed years after exposure as evidenced by survivors of a sarin attack in a Tokyo subway. Independently, pathologic white matter microstructural alterations, inefficient connectivity in the limbic system and default mode network (DMN) reductions have been observed in animal models of induced SE. However, the effect of OP exposure on white matter microstructure and underlying pathophysiological mechanism(s) are unknown. Our approach examines pathologic white matter microstructural alterations after DFP exposure. We will use high resolution diffuse tensor imaging (DTI) to analyze SE-induced deleterious effects. In addition to determining pathphysiological effects of DFP, we will also perform an intervention. We will test the anti-excitotoxic and anti-inflammatory efficacy of alpha-linolenic acid (LIN) to prevent the DFP-induced pathologic white matter microstructural alterations and reduction in the DMN by employing DTI and functional magnetic resonance imaging (FMRI) on a 7T MRI. Finally, we will perform target and off-target lipidomics to gain insight into the contributions of pro- and anti-inflammatory polyunsaturated fatty acid-derived oxylipins in OP-induced white matter changes. The data acquired in this study will define the pathologic white matter microstructural alterations and reduction in the DMN after DFP exposure. We will also understand mechanisms underlying DFP-induced effects. The incorporation of a pharmaco- intervention may prevent the white matter microstructural damage and DMN reduction after OP exposure. LIN derived oxyipins may tip the balance toward an anti-inflammatory state in brain to increase neuronal connectivity function and improve clinical outcome.


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: 2026 ( Subtotal = $0 )
2026	2025	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/4/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $224,146 )
2025	2025	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/1/2025	NON-COMPETING CONTINUATION	$224,146
														Subtotal = $224,146

Issue Date FY: 2024 ( Subtotal = $254,408 )
2024	2024	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/16/2024	NEW	$0
2024	2024	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/1/2024	NEW	$254,408
														Subtotal = $254,408

Grand Total All Awards = $478,554

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Inflammation and white matter microstructural alterations after OP exposure

Award Number: R21NS136126

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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