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。项目1将 使用一个成熟的急性DFP中毒大鼠模型来检验促进DFP中毒的治疗的假设。 当作为标准治疗的替代品给药时，炎症的消退将减轻长期的不良反应， 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）急性OP中毒引发了多个神经系统的强烈神经炎症反应， 持续长达6个月的大脑区域;和（2）促炎信号与 癫痫发生和认知功能障碍。我们将集中我们的初步努力，脂质介质 炎症。我们对DFP急性中毒大鼠脑脂质组的分析表明， 治疗方法：抑制环氧合酶-2（考克斯-2）以阻断胡萝卜素的形成，和 抑制可溶性环氧化物水解酶（sEH）以稳定抗炎脂质介质。一个小 加州大学戴维斯分校开发的sEH分子抑制剂（sEHI）已显示出显著减弱 毛果芸香碱诱导癫痫的临床前模型，改善阿尔茨海默病临床前模型的认知功能 疾病（AD），并减少AD、中风和帕金森病模型中的病理学。我们的初步数据 表明sEHI也减轻神经炎症并终止大鼠DFP模型中的SRS。我们的目标是： (1)描述急性DFP后雄性和雌性大鼠神经炎症的时空特征 中毒，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)评估神经保护 在雄性和雌性大鼠中sEHI和其它靶向失调的炎症介质的化合物的功效 急性中毒(3)确定治疗电极导线的安全性及其在保护 对抗急性梭曼中毒大鼠模型中的不良神经学后果。如果成功，项目1 将确定新型治疗电极导线，用于治疗时可改善长期神经学结局， 护理标准，以及识别发生SRS和/或SRS风险增加的个体的生物标志物 急性OP中毒后的认知功能障碍。