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: 10852175
• 负责人: Amy R. Brooks-Kayal
• 金额: $ 8.85万
• 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/10852175
• 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.

项目摘要 - 总体 新的加州大学戴维斯分校抵抗卓越中心的主要目标是识别和发展新颖 治疗策略是作为现场护理标准（SOC）治疗的辅助策略 急性有机磷酸盐（OP）中毒将减轻长期，逆境的发作和/或严重程度 神经系统后果。该中心的总体假设是治疗策略 减少大脑的炎症，保护血脑屏障（BBB）功能和/或归一化神经元 兴奋性将比单独使用SOC改善长期神经系统结果更有效。当前的医疗 对策可以降低毒素感染者的死亡率，但他们不提供防止 除非在 曝光分钟，如果发生意外，自杀或与恐怖分子有关的情况，这是不太可能的情况 暴露。这些限制强调了迫切需要改善医疗对策。中心 由三个研究项目组成：项目1将评估减少新的治疗候选者 神经炎症；项目2将评估保护BBB功能的策略；项目3将测试 使神经元令人兴奋的正常化的药理和电生理策略。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，医学 化学，配方和PK研究；神经成像核心将在体内和高体内提供临床前 成像；统计核心将支持实验设计和数据分析。研究教育 核心将在对策研究中提供培训，行政核心将作为中心的 枢纽和管理新兴的科学和科学家试点项目计划。中心将使用两个 急性OP氧化的临床前模型：用二异丙基氟磷酸盐的急性氧化大鼠模型 （DFP）和急性SOMAN中毒的大鼠模型，这些模型概括了急性（胆碱能危机和状态） 癫痫症）和慢性（进行性神经病理学，自发性癫痫发作（SRS）和认知 在人类中观察到的障碍）用OP急性陶醉。我们在这个第一个项目时期的目标是： （1）根据慢性，逆境的发病机理的机理研究确定新型热目标 急性OP中毒的神经系统作用。 （2）培养治疗候选者，当单独给予或在 组合作为SOC预防或减轻慢性神经毒性的辅助疗法。治疗候选人包括 新型的小分子抑制剂的固体环氧水解酶（SEH），纤溶酶原激活剂抑制剂1（PAI-1）或 钙蛋白酶； KCA通道激活剂；和FDA批准的疗法（IL-1β阻滞剂，离子通道调节剂和深度 大脑刺激）。 （3）识别生物标志物（血传播分子以及脑电生理学， 神经影像学和行为指数）可以转化为临床用途，以预测 暴露的个体中的SR和认知功能障碍。

项目成果

Enhancement of the liver's neuroprotective role ameliorates traumatic brain injury pathology.

• DOI: 10.1073/pnas.2301360120
• 发表时间: 2023-06-27
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Dai, Yongfeng;Dong, Jinghua;Wu, Yu;Zhu, Minzhen;Xiong, Wenchao;Li, Huanyu;Zhao, Yulu;Hammock, Bruce D.;Zhu, Xinhong
• 通讯作者: Zhu, Xinhong