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.

项目概要-总体 新的加州大学戴维斯分校反ACT卓越中心的主要目标是识别和开发新的 作为现场标准治疗（SOC）治疗的辅助治疗策略， 急性有机磷（OP）中毒将减轻长期不良反应的发生和/或严重程度， 神经学后果。该中心的首要假设是， 减少脑中的炎症，保护血脑屏障（BBB）功能，和/或使神经元正常化 在改善长期神经学结果方面，兴奋性将比单独的SOC更有效。当前医学 对抗措施可以降低OP中毒个体的死亡率，但它们不能提供保护， 与急性OP中毒相关的长期神经系统后遗症，除非在 在发生意外、自杀或与恐怖主义有关的事件时， 暴露。这些局限性突出表明迫切需要改进医疗对策。中心 包括三个研究项目：项目1将评估新的治疗候选人，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 用于使神经元兴奋性正常化的药理学和电生理学策略。三大科学核心 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、制剂和PK研究; Neuroimaging Core将提供临床前体内和高含量的 统计核心将支持实验设计和数据分析。研究性教育 核心将提供对策研究方面的培训，行政核心将作为中心的 中心和管理新兴科学和科学家试点项目计划。该中心将使用两个 急性OP中毒的临床前模型：二异丙基氟磷酸盐急性中毒大鼠模型 (DFP)急性梭曼中毒大鼠模型，再现了急性胆碱能危象和状态 癫痫发作）和慢性（进行性神经病理学、自发性复发性癫痫发作（SRS）和认知功能障碍） 在急性中毒的人中观察到的损伤效应。我们在第一个项目期间的目标是： (1)基于慢性、不良和非典型肺炎发病机制的机制研究， 急性OP中毒的神经学影响。(2)开发治疗候选药物，当单独或联合给药时， 作为SOC的辅助治疗，联合用药可预防或减轻慢性神经毒性。治疗候选药物包括 可溶性环氧化物水解酶（sEH）、纤溶酶原激活物抑制剂-1（派-1）或 钙蛋白酶; KCA通道激活剂;和FDA批准的治疗（IL-1β阻滞剂，离子通道调节剂和深 脑刺激）。(3)识别生物标志物（血液传播的分子，以及脑电生理学， 神经成像和行为指数），可以转化为临床使用，用于预测发展 暴露个体的SRS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