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

加州大学戴维斯分校 CounterACT 卓越中心的多样性补充：JAK/STAT 信号通路在急性有机磷中毒的慢性神经系统影响中的作用

• 批准号: 10834649
• 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/10834649
• 关键词: Acute; Animal Model; Biological Markers; Brain; Chemicals; Chronic; Cognitive; Communities; Convulsants; Data; Drug resistance; Ensure; Event; Face; Female; Generations; Goals; Immunity; Impaired cognition; Individual; Inflammation; Interleukin-1 beta; Intoxication; Isoflurophate; Janus kinase; Knowledge; Life; Memory Loss; Modeling; Morbidity - disease rate; Neurologic; Neurologic Deficit; Neurologic Effect; Neurons; Organophosphates; Outcome; Pathogenesis; Pathway interactions; Patients; Pilocarpine; Preparation; Rattus; Recurrence; Reporting; Research; Research Activity; Role; STAT protein; STAT3 gene; Seizures; Signal Pathway; Signal Transduction; Soman; Status Epilepticus; Survivors; Synaptic plasticity; Technical Expertise; Temporal Lobe Epilepsy; Testing; Therapeutic; Training; Work; career; career networking; chemical threat; disability; effective therapy; experience; improved; inhibitor; lipid mediator; male; mass casualty; medical countermeasure; nerve agent; neuroinflammation; neuroprotection; parent grant; skills; spatiotemporal; standard of care; synaptogenesis; 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 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.

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 假设施用阻断Janus激酶/信号传感器和激活因子的疗法 转录（JAK/STAT）途径作为护理标准的辅助功能将减轻长期不利 急性OP中毒的神经系统后果。该假设的科学前提包括 实验证据表明：（1）最近在 临时叶癫痫； （2）已知该途径参与炎症和免疫力，至关重要 对于神经元功能，例如合成可塑性和突触发生； （3）以前报道了 STAT3抑制剂WP1066可以大大减少一个赞助复发性癫痫发作（SRS）的数量 毛果石诱导的SE的动物模型。这种多样性补充的研究目标是：（1）表征 急性DFP后，雄性和雌性大鼠大脑中JAK/Stat信号的时空轮廓 中毒以确定治疗窗口，并发展可翻译的炎症生物标志物 预测SRS和/或认知功能障碍，以及（2）评估男性WP1066的神经保护效率 雌性大鼠用DFP急性陶醉。这项研究是完整的，并扩展了所描述的研究 在父母赠款中，该赠款集中在神经炎症的脂质介质上，作为治疗靶标。培训 这种多样性补充的目标包括：（1）发展受训者的知识和技术技能，以实现 他们成功地进行医学对策的研究； （2）指导实习生的研究活动 确保支持他们准备竞争性F31应用所需的数据并提高 对于候选人而言，可以告知治疗靶向IL-1β信号以减轻长期的可行性 急性OP中毒的术语不良神经系统后果； （3）提高学员的专业技能； （4）积极与学员合作，建立自己的专业网络，以增强他们的可能性 过渡到学术研究领域的独立职业。