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

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 假设给予阻断Janus激酶/信号转导和激活剂的治疗， 转录（JAK/STAT）途径作为标准治疗的替代品将减轻长期不良反应， 急性OP中毒的神经学后果。这一假设的科学前提包括 实验证据表明：（1）JAK/STAT信号转导最近被牵连在发病机制， 颞叶癫痫;（2）已知该通路参与炎症和免疫，并且是关键的 神经元功能，如突触可塑性和突触发生;和（3）以前报道， STAT 3抑制剂WP 1066可显著减少自发性反复发作（SRS）的次数。 毛果芸香碱诱发SE动物模型。本多样性补充的研究目标是：（1）表征 急性DFP后雄性和雌性大鼠脑中JAK/STAT信号传导的时空分布 中毒，以确定治疗窗口，并开发可翻译的炎症生物标志物， 预测SRS和/或认知功能障碍和（2）评估WP1066在男性和女性中的神经保护功效。 DFP急性中毒的雌性大鼠。本研究是对上述研究的补充和延伸 在父母补助金，这是集中在脂质介质的神经炎症作为治疗目标。培训 本多样性补充的目标包括：（1）发展受训者的知识和技术技能， （2）指导学员的研究活动， 确保生成所需的数据，以支持他们准备有竞争力的F31应用程序，并推进 候选资格，以及告知治疗靶向IL-1β信号传导以减轻长期 （3）提高受训者的专业技能; 和（4）积极与学员合作，建立他们的专业网络，以提高他们的可能性 过渡到学术研究的独立职业。

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.