Project 1: Reduction of Pro-Inflammatory Signaling

项目 1：减少促炎症信号传导

• 批准号: 10684082
• 负责人: Pamela J Lein
• 金额: $ 49.11万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684082
• 关键词: Acute; Address; Adult; Adverse effects; Alzheimer' s disease model; Animals; Anti-Inflammatory Agents; Astrocytes; Atropine; Attenuated; Behavior; Behavior assessment; Benzodiazepines; Biological Markers; Blood; Blood brain barrier dysfunction; Brain; Brain region; Chemicals; Chronic; Clinical; Cognitive; Cognitive deficits; Collaborations; Convulsants; Coxibs; Cyclic AMP; Data; Development; Dose; Electroencephalography; Enzyme Inhibition; Epilepsy; Epileptogenesis; Epoxide hydrolase; FDA approved; Face; Female; Gliosis; Goals; HMGB1 gene; Histology; Homologous Gene; Human; IL8 gene; Impaired cognition; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-6; Intoxication; Isoflurophate; Laboratories; Lead; Life; Link; Magnetic Resonance Imaging; Measures; Medical Research; Memory Loss; Microglia; Minocycline; Modeling; Monitor; Morbidity - disease rate; Motor; Natural History; Nerve Degeneration; Neurologic; Neurologic Deficit; Neurological outcome; Organophosphates; Outcome; Oximes; Parkinson Disease; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Pilocarpine; Positron-Emission Tomography; Pre-Clinical Model; Prostaglandins; Rattus; Recurrence; Research Institute; Resolution; Rest; Risk; STAT3 gene; Safety; Seizures; Signal Transduction; Signaling Molecule; Soman; Status Epilepticus; Stroke; Survivors; Testing; Therapeutic; Treatment Efficacy; acute care; anakinra; antagonist; astrogliosis; chemical threat; cognitive function; cyclooxygenase 2; improved; in vivo imaging; lipid mediator; lipidome; male; medical countermeasure; mineralization; neuroinflammation; neuropathology; neuroprotection; novel therapeutics; predictive marker; prevent; response; small molecule inhibitor; spatiotemporal; standard of care; therapeutic candidate; therapeutic target

Project Summary – Project 1 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. Project 1 will use a well-established rat model of acute DFP intoxication to test the hypothesis that therapies that promote resolution of inflammation when administered 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) acute OP intoxication triggers a robust neuroinflammatory response in multiple brain regions that persists for up to 6 months; and (2) pro-inflammatory signaling is causally linked to epileptogenesis and cognitive dysfunction in non-OP models. We will focus our initial efforts on lipid mediators of inflammation. Our analyses of the brain lipidome in rats acutely intoxicated with DFP suggests two potential therapeutic approaches: inhibiting cyclooxygenase-2 (COX-2) to block the formation of prostaglandins, and inhibiting the enzyme soluble epoxide hydrolase (sEH) to stabilize anti-inflammatory lipid mediators. A small molecule inhibitor of sEH (sEHI) developed at UC Davis has been shown to significantly attenuate SRS in preclinical models of pilocarpine-induced epilepsy, improve cognitive function in preclinical models of Alzheimer’s disease (AD), and reduce pathology in models of AD, stroke and Parkinson’s disease. Our preliminary data suggest that sEHI also mitigates neuroinflammation and terminates SRS in the rat DFP model. Our goals are to: (1) Characterize the spatiotemporal profile of neuroinflammation in male and female rats following acute DFP intoxication in order to identify therapeutic targets, determine therapeutic windows, and develop translatable biomarkers of inflammation that predict SRS and/or cognitive dysfunction. (2) Evaluate the neuroprotective efficacy of sEHI and other compounds that target dysregulated inflammatory mediators in male and female rats acutely intoxicated with DFP. (3) Determine the safety of therapeutic lead(s) and their efficacy in protecting against adverse neurological consequences in a rat model of acute soman intoxication. If successful, Project 1 will identify novel therapeutic lead(s) that improve long-term neurological outcomes when used as adjuncts to standard of care, as well as biomarkers that identify individuals at increased risk for developing SRS and/or cognitive deficits following acute OP intoxication.

项目摘要-项目1 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。项目1将 使用一种公认的急性DFP中毒的大鼠模型来检验这样的假设，即促进 作为标准护理的辅助用药，炎症的消退将减轻长期的不良反应 急性有机磷农药中毒的神经后果。这一假设的科学前提包括 实验证据表明：(1)急性有机磷农药中毒在多发性硬化患者中触发了强烈的神经炎性反应。 持续长达6个月的大脑区域；以及(2)促炎信号与 非OP模型的癫痫发生和认知功能障碍。我们将把最初的工作重点放在脂质调节剂上。 发炎的症状。我们对DFP急性中毒大鼠脑内脂体的分析提出了两个潜在的可能性 治疗方法：抑制环氧合酶-2(COX-2)以阻断前列腺素的形成，以及 抑制酶溶环氧化物水解酶(SEH)以稳定抗炎脂质介体。一小块 加州大学戴维斯分校开发的sEH分子抑制剂(SEHI)已被证明可显著减弱SRS。 匹罗卡品诱发癫痫的临床前模型，改善阿尔茨海默病临床前模型的认知功能 治疗阿尔茨海默病(AD)，减少AD、中风和帕金森氏病模型的病理改变。我们的初步数据 提示sEHI还可减轻DFP模型大鼠的神经炎症反应并终止SRS。我们的目标是： (1)急性DFP后雄性和雌性大鼠神经炎症的时空分布特征 醉酒，以确定治疗目标，确定治疗窗口，并开发可翻译的 预测SRS和/或认知功能障碍的炎症生物标志物。(2)评价神经保护作用 SEHI等靶向炎症介质失调的化合物对雄性和雌性大鼠的作用 极度沉醉于DFP。(3)确定治疗性铅的安全性(S)及其保护效果 对抗急性梭曼中毒大鼠模型的不良神经后果。如果成功，项目1 将确定新的治疗铅(S)，当用作辅助治疗时，可以改善长期神经学结果 护理标准，以及识别发生SRS和/或发生SRS风险增加的个人的生物标志物 急性有机磷农药中毒后的认知缺陷。