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

加州大学戴维斯分校 CounterACT 卓越中心的多样性补充：IL-1β 在介导急性有机磷中毒的慢性不良神经学影响中的作用。

• 批准号: 10837432
• 负责人: Amy R. Brooks-Kayal
• 金额: $ 1.48万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10837432
• 关键词: Acute; Acute Disease; Adolescent; Antiepileptogenic; Autoimmune Diseases; Biological Markers; Brain; Chemicals; Chronic; Chronic Phase of Disease; Clinical; Clinical Trials; Cognitive; Communities; Convulsants; Data; Drug resistance; Ensure; Epilepsy; Epileptogenesis; Etiology; Event; Experimental Models; Face; Female; Fever; Generations; Goals; Human; IL1R1 gene; Impaired cognition; Individual; Infection; Inflammation; Inflammatory; Interleukin-1 beta; Intoxication; Isoflurophate; Knowledge; Life; Mediating; Memory Loss; Modeling; Morbidity - disease rate; Neurologic; Neurologic Deficit; Neurologic Effect; Organophosphates; Outcome; Patients; Preparation; Rattus; Recombinants; Recurrence; Research; Research Activity; Role; Seizures; Signal Transduction; Soman; Status Epilepticus; Survivors; Syndrome; TBI Patients; Technical Expertise; Testing; Therapeutic; Training; Work; anakinra; antagonist; career; career networking; chemical threat; disability; effective therapy; experience; improved; lipid mediator; male; mass casualty; medical countermeasure; nerve agent; neuroinflammation; neuroprotection; parent grant; skills; spatiotemporal; standard of care; therapeutic target; therapeutically effective

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.

抽象的 抽搐的化学威胁药，例如有机磷酸盐（OPS）二异丙氟磷酸酯（DFP）和 索曼（Soman）可以触发癫痫发作，这些癫痫发作会发展为威胁生命的癫痫持续状态（SE）。幸存者面临着重要的 长期发病率，包括自发的复发性癫痫发作（SRS）和轻度至重度记忆丧失。当前的 医学对策无法正确防止这些长期神经系统缺陷。工作 在这种多样性中描述的补充剂将使用急性DFP侵入性的良好大鼠模型来测试 假设施用将白介素-1β（IL-1β）信号作为标准辅助的疗法 小心将减轻急性OP中毒的长期不良神经系统后果。科学 该假设的前提包括：（1）IL-1β水平可预测的临床和实验证据。 脑损伤患者的癫痫发生； （2）Anakinra，一种市售的重组人 在实验模型中，用于治疗自身免疫性疾病的IL-1R拮抗剂（IL1RA）具有抗癫痫发作。 （3） 在临床试验中，阿纳基纳（Anakinra 火灾（与热感染相关的癫痫综合征）； （4）Anakinra减少了耐药性癫痫发作 患有癫痫的青少年与炎症病因相关。这种多样性的研究目标 补充是：（1）表征男性和女性大脑中IL-1β信号传导的时空特征 急性DFP氧气后的大鼠为了确定治疗窗口并开发可翻译的窗户 预测SR和/或认知功能障碍的炎症生物标志物，（2）评估神经保护 Anakinra在雄性和雌性大鼠中的功效用DFP急性陶醉。这项研究是完整的 并扩展了父母赠款中描述的研究，该研究的重点是神经炎症的脂质介质 作为治疗靶标。这种多样性补充的培训目标包括：（1）发展受训者的 设定的知识和技术技能，使他们能够成功进行医学对策的研究； （2）指导学员的研究活动，以确保支持他们准备的所需数据 具有竞争力的F31应用程序并提高了候选人，并为理论的可行性提供了信息 靶向IL-1β信号传导以减轻急性OP触犯的长期不良神经系统后果； （3）提高学员的专业技能； （4）积极与学员合作以建立自己的专业人士 网络可以增强其过渡到学术研究独立职业的可能性。