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 惊厥化学威胁剂，如有机磷(OPS)二异丙基氟磷酸盐(DFP)和 梭曼，可引发癫痫发作，进展为危及生命的癫痫状态(SE)。幸存者面临着重大的、 长期发病率，包括自发性反复发作(SRS)和轻度至严重的记忆力丧失。当前 医学对策未能充分保护这些长期的神经缺陷。这项工作 将使用已建立的急性DFP中毒的大鼠模型来测试 假设将拮抗IL-1β(IL-1β)信号的治疗作为标准的辅助手段 护理将减轻急性OP中毒的长期不良神经后果。科学的 这一假设的前提包括临床和实验证据：(1)IL-1β水平可以预测 创伤性脑损伤患者的癫痫发生；(2)Anakinra，一种商业化的重组人 白介素1受体拮抗剂(IL1Ra)用于治疗自身免疫性疾病，在实验模型中具有抗癫痫作用； 在临床试验中，Anakinra成功地减少了急性和慢性病阶段的持续癫痫发作 火灾(发热性感染相关癫痫综合征)；和(4)阿纳金纳减少耐药癫痫发作 青少年癫痫与炎症性病因有关。这种多样性的研究目标 补充如下：(1)表征IL-1β信号在男女脑中的时空分布 大鼠急性DFP中毒后，以确定治疗窗口，并开发可翻译 预测SRS和/或认知功能障碍的炎症生物标志物以及(2)评估神经保护 阿纳金纳对DFP急性中毒雌雄大鼠的疗效。这项研究是对 并扩展了家长资助中描述的研究，该研究侧重于神经炎症的脂质介质 作为治疗靶点。本多元化副刊的培训目标包括：(1)发展学员的 能够成功地进行医学对策研究的知识和技能； (2)指导学员的研究活动，确保生成必要的数据，以支持他们准备 竞争激烈的F31申请和候选人资格的晋级，也是治疗上的可行性 靶向IL-1β信号以减轻急性OP中毒的长期不良神经后果； (3)提高学员的专业技能；及(4)积极与学员合作，建立他们的专业 网络，以提高他们过渡到独立的学术研究生涯的可能性。

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.