High-throughput in vivo discovery of novel countermeasures against organophosphate-induced seizure and status epilepticus using zebrafish
利用斑马鱼高通量体内发现针对有机磷诱发的癫痫发作和癫痫持续状态的新对策
基本信息
- 批准号:10588158
- 负责人:
- 金额:$ 26.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AcousticsAcridine OrangeAddressAnimal ModelAntiepileptic AgentsApoptoticAtropineBiological AssayCalciumCaringCellsChemical ExposureChemical WeaponsChemicalsChlorpyrifosClinicalComplicationDataDetectionDiseaseDoseDrug ScreeningElectrophysiology (science)EventExposure toFDA approvedFluorescenceFunctional disorderGeneralized EpilepsyGeneticHumanIntoxicationLevetiracetamLiteratureLorazepamMaximum Tolerated DoseMeasuresMedicalMemantineModelingMolecularMonitorOrganophosphatesParathionPesticidesPharmaceutical PreparationsPhoratePropertyPublic HealthResearchSarinSedation procedureSeizuresSomanStandardizationStartle ReactionStatus EpilepticusTdT-Mediated dUTP Nick End Labeling AssayTimeValidationVisualWhole OrganismWorkZebrafishacute toxicityblindcandidate identificationchemical threatexcitotoxicityexperimental studyexposed human populationhigh throughput screeningimprovedin vivomass casualtymedical countermeasurenerve agentnovelprogramsreal world applicationresearch clinical testingresponsescreeningsedativetabuntherapeutic candidatetherapy development
项目摘要
PROJECT SUMMARY
Chemical threats are a major public health concern and CounterACT recognizes the need to identify new
medical countermeasures (MCMs) that improve the public health response to mass casualty events related to
chemical threats. Organophosphate (OP) agents are of particular concern due to their wide availability in
common pesticides and their use in chemical nerve agents. OP-induced seizures are a serious consequence
of OP-intoxication and best agents for treating this complication are unclear. Major gaps include limited
opportunities for systematic clinical evaluations in humans prior to mass casualty, drawbacks to existing
medication, which may not control seizures or excitotoxicity, and worsen sedation; and lack of direction in
discovering new MCMs. To address these gaps, we propose to characterize a zebrafish model of OP-induced
seizures and excitotoxicity using chlorpyrifos-oxon (CPO)1 – an active metabolite of the common OP pesticide,
chlorpyrifos -- and to advance its use for high-throughput compound screening to identify novel MCMs against
OP-induced seizures and excitotoxicity. In Aim 1, we will characterize a larval zebrafish model of CPO-induced
seizure and optimize parameters for the identification of novel countermeasures. In Aim 1A, we will confirm
seizure activity using both electrophysiology (EEG) as well as noninvasive measures based on calcium
fluorescence. In addition, we will assess survival and excitotoxicity as evidenced by the burden of apoptotic
cells following seizures using TUNEL assay and less time-intensive acridine orange (AO) assay. In Aim 1B,
we will identify the ideal assay parameters for detecting novel countermeasures to CPO-induced seizures by
identifying the maximum tolerated dose in larval zebrafish of existing countermeasures followed by a CPO
dose-response experiment to identify the conditions that result in 25-50% reduction in CPO-induced seizures
versus control. This target is chosen to allow detection of the effect of existing countermeasures while
providing dynamic range for the detection of superior countermeasures. In Aim 1C, we will quantify sedation
as a function of anti-seizure activity in conventional AEDs, by establishing ED50 for several AEDs in response
to CPO-induced seizures; these data will be compared to the sedative effect of AEDs in the visual startle
response (VSR) and acoustic startle response (ASR) assays. Finally, in Aim 2, we will implement a whole
organism compound screen for novel MCMs against OP-induced seizure and excitotoxicity, and prioritize hits
based on ranked paired robust strictly standardized mean difference (SSMD*) and least sedating effects.
Taken together, this exploratory R21 is responsive to multiple facets of the CounterACT program and provides
a framework for whole organism in vivo discovery of novel countermeasures against CPO that may be
extended to additional OP agents.
项目总结
项目成果
期刊论文数量(0)
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{{ truncateString('Christopher McGraw', 18)}}的其他基金
High-throughput in vivo discovery of novel countermeasures against organophosphate-induced seizure and status epilepticus using zebrafish
利用斑马鱼高通量体内发现针对有机磷诱发的癫痫发作和癫痫持续状态的新对策
- 批准号:
10457138 - 财政年份:2022
- 资助金额:
$ 26.46万 - 项目类别:
Developing a Zebrafish Model of Slc6a1/GAT1 Hypofunction and an In Vitro Assay to Identify Novel Treatments
开发 Slc6a1/GAT1 功能减退的斑马鱼模型以及识别新疗法的体外测定
- 批准号:
10646493 - 财政年份:2020
- 资助金额:
$ 26.46万 - 项目类别:
Developing a zebrafish model of Slc6a1/GAT1 hypofunction and an in vitro assay to identify novel treatments
开发 Slc6a1/GAT1 功能减退的斑马鱼模型和体外测定以确定新的治疗方法
- 批准号:
10041423 - 财政年份:2020
- 资助金额:
$ 26.46万 - 项目类别:
Developing a zebrafish model of Slc6a1/GAT1 hypofunction and an in vitro assay to identify novel treatments
开发 Slc6a1/GAT1 功能减退的斑马鱼模型和体外测定以确定新的治疗方法
- 批准号:
10427320 - 财政年份:2020
- 资助金额:
$ 26.46万 - 项目类别:
Developing a zebrafish model of Slc6a1/GAT1 hypofunction and an in vitro assay to identify novel treatments
开发 Slc6a1/GAT1 功能减退的斑马鱼模型和体外测定以确定新的治疗方法
- 批准号:
10215638 - 财政年份:2020
- 资助金额:
$ 26.46万 - 项目类别:
Investigating the homeostatic role of MeCP2 in mature brain
研究 MeCP2 在成熟大脑中的稳态作用
- 批准号:
8060117 - 财政年份:2011
- 资助金额:
$ 26.46万 - 项目类别:
Investigating the homeostatic role of MeCP2 in mature brain
研究 MeCP2 在成熟大脑中的稳态作用
- 批准号:
8261974 - 财政年份:2011
- 资助金额:
$ 26.46万 - 项目类别:
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