UC Davis CounterACT Center of Excellence: Developing Therapeutic Strategies for Mitigating the Chronic Neurological Consequences of Acute Organophosphate Intoxication

加州大学戴维斯分校 CounterACT 卓越中心：制定缓解急性有机磷中毒慢性神经系统后果的治疗策略

• 批准号: 10684066
• 负责人: Amy R. Brooks-Kayal
• 金额: $ 273万
• 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/10684066
• 关键词: Accidents; Acute; Address; Adult; Analytical Chemistry; Area; Atropine; Automobile Driving; Behavioral; Benzodiazepines; Biological Markers; Brain; Brain Injuries; Calpain; Cessation of life; Cholinesterase Inhibitors; Chronic; Clinical; Data; Data Analyses; Deep Brain Stimulation; Detection; Development; Disease; Electrophysiology (science); Epilepsy; Epoxide hydrolase; Event; Experimental Designs; Exposure to; FDA approved; Female; Formulation; Goals; Hour; Human; Image; Impaired cognition; Impairment; Individual; Industrial Accidents; Inflammation; Intellectual Property; Interleukin-1 beta; Intervention; Intoxication; Ion Channel; Isoflurophate; Learning; Life; Link; Memory; Mentors; Modeling; Molecular; Morbidity - disease rate; Nerve Degeneration; Nervous System Physiology; Neurologic; Neurologic Effect; Neurological outcome; Organophosphates; Outcome; Oximes; Pathogenesis; Pathogenicity; Pathway interactions; Pesticides; Pharmaceutical Chemistry; Phase; Pilot Projects; Plasminogen Activator Inhibitor 1; Pre-Clinical Model; Rattus; Recurrence; Research; Research Personnel; Research Project Grants; Risk; Rodent; Science; Scientist; Seizures; Severities; Signal Transduction; Soman; Status Epilepticus; Survivors; Testing; Therapeutic; Toxic effect; Training; Translating; United States National Institutes of Health; biomarker identification; blood-brain barrier function; candidate identification; cholinergic; combinatorial; education research; equity, diversity, and inclusion; experience; forging; improved; in vivo; indexing; innovation; male; mass casualty; medical countermeasure; meetings; mortality; multidisciplinary; nerve agent; neuroimaging; neuroinflammation; neuronal excitability; neuropathology; neurotoxic; neurotoxicity; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; pre-clinical; preclinical study; predictive marker; prevent; programs; recruit; response; small molecule inhibitor; standard of care; statistics; suicidal; therapeutic candidate

Project Summary – Overall The primary objective of the new UC Davis CounterACT Center of Excellence is to identify and develop novel therapeutic strategies that when administered as an adjunct to in-field standard of care (SOC) treatments for acute organophosphate (OP) intoxication will mitigate the onset and/or severity of long-term, adverse neurological consequences. The overarching hypothesis of the Center is that therapeutic strategies that reduce inflammation in the brain, protect blood-brain barrier (BBB) function, and/or normalize neuronal excitability will be more effective than SOC alone in improving long-term neurological outcomes. Current medical countermeasures can reduce mortality in OP-intoxicated individuals, but they do not provide protection against the long-term neurological sequelae associated with acute OP intoxication unless they are administered within minutes of exposure, which is an unlikely scenario in the event of accidental, suicidal or terrorist-related exposures. These limitations underscore the urgent need for improved medical countermeasures. The Center consists of three Research Projects: Project 1 will evaluate novel therapeutic candidates that reduce neuroinflammation; Project 2 will assess strategies for protecting BBB function; and Project 3 will test pharmacologic and electrophysiologic strategies for normalizing neuronal excitability. Three Scientific Cores support the Projects: the Analytical and Medicinal Chemistry Core will support biomarker detection, medicinal chemistry, formulation and PK studies; the Neuroimaging Core will provide preclinical in vivo and high-content imaging; and the Statistics Core will support experimental design and data analyses. A Research Education Core will provide training in countermeasure research, and an Administrative Core will function as the Center’s hub and administer the Emerging Science and Scientists Pilot Project Program. The Center will use two preclinical models of acute OP intoxication: the rat model of acute intoxication with diisopropylfluorophosphate (DFP) and the rat model of acute soman intoxication, which recapitulate the acute (cholinergic crisis and status epilepticus) and chronic (progressive neuropathology, spontaneous recurrent seizures (SRS) and cognitive impairment) effects observed in humans acutely intoxicated with OPs. Our goals in this 1st project period are to: (1) Identify novel therapeutic targets based on mechanistic studies of the pathogenesis of chronic, adverse neurological effects of acute OP intoxication. (2) Develop therapeutic candidates that when given singly or in combination as adjunct therapy to SOC prevent or mitigate chronic neurotoxicity. Therapeutic candidates include novel small molecule inhibitors of soluble epoxide hydrolase (sEH), plasminogen activator inhibitor-1 (PAI-1), or calpain; KCA channel activators; and FDA-approved therapies (IL-1β blocker, ion channel modulators and deep brain stimulation). (3) Identify biomarkers (blood-borne molecules, as well as brain electrophysiology, neuroimaging and behavioral indices) that can be translated to clinical use for predicting the development of SRS and cognitive dysfunction in exposed individuals.

项目总结 – 总体 新的加州大学戴维斯分校 CounterACT 卓越中心的主要目标是识别和开发新颖的 治疗策略，作为现场标准护理 (SOC) 治疗的辅助手段 急性有机磷（OP）中毒将减轻长期不良反应的发作和/或严重程度 该中心的首要假设是治疗策略 减少大脑炎症，保护血脑屏障（BBB）功能，和/或使神经元正常化 在改善长期神经系统结果方面，兴奋性比单独使用 SOC 更有效。 对策可以降低OP中毒者的死亡率，但不能提供预防措施 与急性 OP 中毒相关的长期神经系统后遗症，除非在 分钟的暴露时间，如果发生意外、自杀或恐怖分子相关事件，这种情况是不太可能发生的 这些限制凸显了该中心迫切需要改进的医疗对策。 由三个研究项目组成：项目 1 将评估新的治疗候选药物，以减少 神经炎症；项目 2 将评估保护 BBB 功能的策略；项目 3 将测试 使神经兴奋性正常化的药理学和电生理策略。三个科学核心。 支持项目：分析和药物化学核心将支持生物标志物检测、药物 化学、配方和药代动力学研究；神经影像核心将提供临床前体内和高含量的研究 成像；统计核心将支持实验设计和数据分析。 核心将提供对策研究方面的培训，行政核心将充当该中心的职能 该中心将使用两个中心并管理新兴科学和科学家试点项目计划。 急性OP中毒临床前模型：二异丙基氟磷酸盐急性中毒大鼠模型 （DFP）和急性梭曼中毒大鼠模型，概括了急性（胆碱能危机和状态） 癫痫）和慢性（进行性神经病理学、自发性复发性癫痫发作 (SRS) 和认知 在严重中毒的人中观察到的损伤）影响我们在第一个项目期间的目标是： (1) 根据慢性、不良疾病发病机制的机制研究确定新的治疗靶点 (2) 开发单独或联合给药的候选治疗药物 作为 SOC 的辅助治疗预防或减轻慢性神经毒性的联合治疗包括。 可溶性环氧化物水解酶 (sEH)、纤溶酶原激活剂抑制剂-1 (PAI-1) 的新型小分子抑制剂，或 钙蛋白酶；KCA 通道激活剂；以及 FDA 批准的疗法（IL-1β 阻滞剂、离子通道调节剂和深层疗法） (3) 识别生物标志物（血源性分子，以及脑电生理学， 神经影像和行为指数），可以转化为临床用途，用于预测疾病的发展 SRS 和暴露个体的认知功能障碍。