Diversity Supplement to UC Davis CounterACT Center of Excellence: Role of IL-1β in mediating the chronic adverse neurological effects of acute organophosphate intoxication.

点击翻译按钮获取中文摘要

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 antagonize interleukin-1β (IL-1β) signaling 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 clinical and experimental evidence that: (1) IL-1β levels are predictive of epileptogenesis in patients with traumatic brain injury; (2) Anakinra, a commercially available recombinant human IL-1R antagonist (IL1Ra) used to treat autoimmune disorders, is anti-epileptogenic in experimental models; (3) In clinical trials, anakinra successfully reduced unremitting seizures in both the acute and chronic disease phases of FIRES (Febrile Infection-Related Epilepsy Syndrome); and (4) Anakinra reduced drug-resistant seizures in adolescents with epilepsy associated with an inflammatory etiology. The research goals of this Diversity supplement are to: (1) Characterize the spatiotemporal profile of IL-1β 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 anakinra 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.