[R01] JAK/STAT signaling as a therapeutic target to mitigate long-term effects of acute organophosphate intoxication

Ente: National Institute of Neurological Disorders and Stroke

Scadenza: 2029-07-31

Importo max: 468.559 EUR

Paese: US

Descrizione

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. Istituzione: UNIVERSITY OF CALIFORNIA AT DAVIS PI: Amy R. Brooks-Kayal, Pamela J Lein Progetto: 1R01NS151264-01

Settori: National Institute of Neurological Disorders and Stroke

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