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

摘要 惊厥性化学威胁剂，如有机磷酸盐（OP）二异丙基氟磷酸盐（DFP）和 梭曼可引发癫痫发作，发展为危及生命的癫痫持续状态（SE）。幸存者面临着重大的， 长期发病率，包括自发性复发性癫痫发作（SRS）和轻度至重度记忆丧失。电流 医疗对策不能充分防止这些长期的神经缺陷。工作 本多样性补充中所述的方法将使用一种成熟的急性DFP中毒大鼠模型来测试 假设给予拮抗白细胞介素-1 β（IL-1β）信号传导的疗法作为对标准IL-1β抑制剂， 护理将减轻急性OP中毒的长期不良神经后果。科学 这一假设的前提包括临床和实验证据：（1）IL-1β水平预测 创伤性脑损伤患者的癫痫发生;（2）Anakinra，一种市售的重组人 IL-1 R拮抗剂（IL 1 Ra）用于治疗自身免疫性疾病，在实验模型中具有抗癫痫作用;（3） 在临床试验中，阿那白滞素成功地减少了急性和慢性疾病阶段的持续癫痫发作 的FIRES（发热性惊厥相关癫痫综合征）;和（4）阿那白滞素减少耐药性癫痫发作， 与炎性病因相关的青少年癫痫。多样性的研究目标 补充如下：（1）描述了IL-1β信号在男性和女性脑中的时空分布 大鼠急性DFP中毒，以确定治疗窗口，并制定翻译 预测SRS和/或认知功能障碍的炎症生物标志物，和（2）评估神经保护性 阿那白滞素对DFP急性中毒雌雄大鼠疗效观察这项研究是对 并扩展了父母资助中描述的研究，该研究集中在神经炎症的脂质介质上 作为治疗靶点。本多元化补充材料的培训目标包括：（1）培养学员的 使他们能够成功地进行医疗对策研究的知识和技术技能; (2)指导受训者的研究活动，以确保生成支持其准备工作所需的数据。 一个有竞争力的F31申请和候选资格的进展，以及告知治疗的可行性， 靶向IL-1β信号传导以减轻急性OP中毒的长期不良神经学后果; (3)提高受训者的专业技能;及（4）积极与受训者合作， 网络，以提高他们过渡到学术研究的独立职业生涯的可能性。

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.