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JAK/STAT signaling as a therapeutic target to mitigate long-term effects of acute organophosphate intoxication

Award Number: R01NS151264
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: 08/20/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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JAK/STAT signaling as a therapeutic target to mitigate long-term effects of acute organophosphate intoxication - Project Summary: Convulsant chemical threat agents, such as organophosphate (OP) cholinesterase inhibitors, can trigger seizures that progress to life-threatening status epilepticus (SE). Survivors face significant, long-term morbidity, including spontaneous recurrent seizures (SRS) and mild-to-severe memory loss. Current medical countermeasures fail to sufficiently protect against these long-term neurological deficits. To address this therapeutic gap, we will use a well-established rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) to test the hypotheses that: (1) DFP initiates STAT3-driven neuroinflammatory cascades prior to or coincident with epileptogenesis and cognitive decline; and (2) a pharmacological inhibitor of STAT3 administered as an adjunct to standard of care will mitigate the long-term, adverse neurological consequences of acute OP intoxication. The scientific premise for these hypotheses includes experimental evidence that: (1) acute OP intoxication triggers enduring neuropathology, including neurodegeneration and neuroinflammation, in multiple brain regions prior to and coincident with SRS and significant cognitive impairment; (2) acute DFP intoxication increased phosphorylated STAT3 in the brain at acute time points post-exposure; (3) genetic inhibition of neuronal STAT3 signaling in epileptic mice prevents SRS progression and associated memory decline, while rescuing gene networks implicated in epileptogenesis; and (4) the FDA-approved JAK1/2 inhibitor ruxolitinib administered after SE induced by triggers other than OPs suppresses hippocampal STAT3 activation, reduces seizure burden, and improves cognitive outcomes in rats. In Aim 1, we will focus our initial efforts on defining the spatiotemporal dynamics of STAT3 activation. Subsequently, in Aim 2, we will evaluate whether ruxolitinib reduces neuroinflammation, neurodegeneration, seizure burden, and/or memory deficits, integrating molecular, imaging, EEG, and behavioral endpoints. If successful, our work will establish STAT3 as a mechanistic driver of DFP-induced chronic neurotoxicity and justify further studies to advance ruxolitinib as a translatable countermeasure to enhance neurological resilience after OP exposure. Overall, this proposal will inform ONETOX’s mission of developing disease-modifying countermeasures for intoxication with OP nerve agents that improve long-term neurological outcomes when used as adjuncts to standard of care.


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 = $468,559 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/20/2026	NEW	$468,559
														Subtotal = $468,559

Grand Total All Awards = $468,559

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JAK/STAT signaling as a therapeutic target to mitigate long-term effects of acute organophosphate intoxication

Award Number: R01NS151264

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: 08/20/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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