Diversity Supplement to UC Davis CounterACT Center of Excellence: The role of the JAK/STAT signaling pathway in chronic neurological effects of acute organophosphate intoxication

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Abstract Convulsant chemical threat agents, such as the organophosphates (OPs) diisopropylfluorophosphate (DFP) and soman, 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. The work described in this Diversity supplement will use a well-established rat model of acute DFP intoxication to test the hypothesis that administering therapies that block the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway as adjuncts to standard of care will mitigate the long-term, adverse neurological consequences of acute OP intoxication. The scientific premise for this hypothesis includes experimental evidence that: (1) JAK/STAT signaling has recently been implicated in the pathogenesis of temporal lobe epilepsy; (2) this pathway is known to be involved in inflammation and immunity, and to be critical for neuronal functions such as synaptic plasticity and synaptogenesis; and (3) it was previously reported that a STAT3 inhibitor, WP1066, could greatly reduce the number of spontaneous recurrent seizures (SRS) in an animal model of pilocarpine-induced SE. The research goals of this Diversity supplement are to: (1) Characterize the spatiotemporal profile of JAK/STAT signaling in the brain of male and female rats following acute DFP intoxication in order to determine therapeutic windows, and develop translatable biomarkers of inflammation that predict SRS and/or cognitive dysfunction and (2) Evaluate the neuroprotective efficacy of WP1066 in male and female rats acutely intoxicated with DFP. This research is complementary to and extends the research described in the parent grant, which is focused on lipid mediators of neuroinflammation as therapeutic targets. The training goals of this Diversity supplement include: (1) Develop the trainee’s knowledge and technical skill set to enable them to successfully conduct research on medical countermeasures; (2) Guide the trainee’s research activity to ensure the generation of data needed to support their preparation of a competitive F31 application and advance to candidacy, was well as inform the feasibility of therapeutically targeting IL-1β signaling to mitigate the long- term adverse neurological consequences of acute OP intoxication; (3) Enhance the trainee’s professional skills; and (4) Actively work with the trainee to build their professional networks to enhance their likelihood of transitioning to an independent career in academic research.