Exploiting EP2 receptor biology to target seizure-related neuroinflammation selectively
利用 EP2 受体生物学选择性地靶向癫痫相关的神经炎症
基本信息
- 批准号:10570244
- 负责人:
- 金额:$ 52.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAgonistAmygdaloid structureAnimal ModelAnti-Inflammatory AgentsAntiepileptogenicAppearanceAstrocytesAutoimmuneBehavioral AssayBiologyBlood - brain barrier anatomyBrainBrain InjuriesCX3CL1 geneCell SurvivalCellsChronicCognitive deficitsConvulsantsCoupledCre driverCyclic AMPCyclic AMP-Dependent Protein KinasesDevelopmentDimensionsDinoprostoneDiseaseElectroencephalographyElementsEncephalitisEpilepsyEpileptogenesisEventFractalkineFrequenciesHeminHippocampusHourHumanIn VitroIncidenceInfectionInfiltrationInflammationInflammatoryInterleukin-6InterruptionInvadedKnock-outLigandsMediatingMembraneMicrogliaModelingModificationMolecularMusMyelogenousMyeloid CellsN-MethylaspartateNerve DegenerationNeuronal InjuryNeuronsOpen Reading FramesOralOutcomePathway interactionsPeptidesPilocarpinePlayProcessProsencephalonProstaglandin E ReceptorProstaglandin ReceptorProteinsQuantitative Reverse Transcriptase PCRReactionReportingRodentRoleSeizuresSeriesStatus EpilepticusTechnologyTestingTransgenesWestern BlottingWorkantagonistbeta-arrestinbutaprostcell typecyclooxygenase 2cytokineexcitotoxicitygenetic approachin vivokainatemanmonocytenervous system disorderneuroinflammationneuropathologyneuroprotectionneurotoxicitynovelpharmacologicpreventprimary outcomereceptorvirtual
项目摘要
Project Summary
Accumulating evidence in humans and in animal models indicates that inflammation of the brain that
develops after status epilepticus (SE) may play a determinant role in long-term detrimental consequences,
independent of an infection or auto-immune cause. The pathophysiological interactions among the various
inflammatory molecules, and the sequence of events leading to their induction, have not yet been dissected.
Previous work pointed to a role for cyclooxygenase-2 (COX-2) pathways in SE-induced inflammation, and
showed that the EP2 receptor mediates much of the COX-2 effect. Our recent work suggests that PGE2
released from neurons after SE activates EP2 receptors on nearby neurons and myeloid cells, and that EP2
activation on neurons and myeloid cells might cause opposing effects. We hypothesize that EP2 activation
on neurons after SE is neuroprotective, whereas EP2 activation on microglia or invading monocytes results
in cytokine synthesis and subsequent development of epilepsy. Here we use a novel HaloTag technology to
target neurons and myeloid cells separately with EP2 antagonists and agonists to test this hypothesis. Our
specific aims are: 1. To test the hypothesis that pharmacologic block of EP2 receptors on neurons and
myeloid cells has opposing effects after SE. 2. To test the hypothesis that blocking EP2 receptors on myeloid
cells interferes with the process of epileptogenesis. 3. To test the hypothesis that EP2-mediated
neuroprotection involves neuronal EP2 receptors, utilizes a cAMP rather than β-arrestin pathway, and
requires CX3CL1 (fractalkine). To address these aims we employ in vitro culture models and in vivo SE
models with novel EP2 antagonists and agonists targeted by HaloTag to neurons or microglia.
Immunohistochemical, western blot, qRT-PCR, cell viability, EEG and behavioral assays are performed.
项目摘要
在人类和动物模型中积累的证据表明,
癫痫持续状态(SE)后的发展可能在长期有害后果中起决定性作用,
独立于感染或自身免疫原因。各种疾病之间的病理生理学相互作用
炎症分子和导致其诱导的事件序列尚未被剖析。
先前的工作指出环氧合酶-2(考克斯-2)通路在SE诱导的炎症中的作用,
表明EP 2受体介导了考克斯-2的大部分作用。我们最近的研究表明,PGE 2
SE后从神经元释放的EP 2激活附近神经元和骨髓细胞上的EP 2受体,
对神经元和骨髓细胞的激活可能导致相反的效果。我们假设EP 2激活
SE后神经元上的EP 2激活是神经保护性的,而小胶质细胞或侵入的单核细胞上的EP 2激活导致
在细胞因子合成和随后的癫痫发展中的作用。在这里,我们使用一种新颖的HaloTag技术,
用EP 2拮抗剂和激动剂分别靶向神经元和髓样细胞以检验该假设。我们
具体目标是:1.为了验证神经元上EP 2受体的药物阻断和
骨髓细胞在SE后具有相反的作用。2.为了验证阻断髓细胞上的EP 2受体
细胞干扰癫痫发生的过程。3.为了验证EP 2介导的
神经保护涉及神经元EP 2受体,利用cAMP而不是β-抑制蛋白途径,
需要CX 3CL 1(fractalkine)。为了解决这些目标,我们采用体外培养模型和体内SE
使用HaloTag靶向神经元或小胶质细胞的新型EP 2拮抗剂和激动剂的模型。
进行免疫组织化学、蛋白质印迹、qRT-PCR、细胞活力、EEG和行为测定。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('RAYMOND J DINGLEDINE', 18)}}的其他基金
Optimization of EP2 Antagonists for Post-Seizure Cognitive Deficits
针对癫痫发作后认知缺陷的 EP2 拮抗剂的优化
- 批准号:
10467539 - 财政年份:2022
- 资助金额:
$ 52.02万 - 项目类别:
Optimization of EP2 Antagonists for Post-Seizure Cognitive Deficits
针对癫痫发作后认知缺陷的 EP2 拮抗剂的优化
- 批准号:
10732636 - 财政年份:2022
- 资助金额:
$ 52.02万 - 项目类别:
Exploiting EP2 receptor biology to target seizure-related neuroinflammation selectively
利用 EP2 受体生物学选择性地靶向癫痫相关的神经炎症
- 批准号:
10356163 - 财政年份:2020
- 资助金额:
$ 52.02万 - 项目类别:
Exploiting EP2 receptor biology to target seizure-related neuroinflammation selectively
利用 EP2 受体生物学选择性地靶向癫痫相关的神经炎症
- 批准号:
10171930 - 财政年份:2020
- 资助金额:
$ 52.02万 - 项目类别:
Probing the Protective Role of EZH2 in Epilepsy
探讨 EZH2 在癫痫中的保护作用
- 批准号:
10617699 - 财政年份:2019
- 资助金额:
$ 52.02万 - 项目类别:
Probing the Protective Role of EZH2 in Epilepsy
探讨 EZH2 在癫痫中的保护作用
- 批准号:
10398140 - 财政年份:2019
- 资助金额:
$ 52.02万 - 项目类别:
Inflammatory control of blood-brain barrier integrity and epileptogenesis after seizures
癫痫发作后血脑屏障完整性和癫痫发生的炎症控制
- 批准号:
9272954 - 财政年份:2016
- 资助金额:
$ 52.02万 - 项目类别:
Inflammatory control of blood-brain barrier integrity and epileptogenesis after seizures
癫痫发作后血脑屏障完整性和癫痫发生的炎症控制
- 批准号:
9914359 - 财政年份:2016
- 资助金额:
$ 52.02万 - 项目类别:
Inflammatory control of blood-brain barrier integrity and epileptogenesis after seizures
癫痫发作后血脑屏障完整性和癫痫发生的炎症控制
- 批准号:
9159612 - 财政年份:2016
- 资助金额:
$ 52.02万 - 项目类别:
Regulation of epileptogenesis by the transcriptional repressor, REST
转录抑制因子 REST 对癫痫发生的调节
- 批准号:
8325008 - 财政年份:2011
- 资助金额:
$ 52.02万 - 项目类别:
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