Endothelial monoamine neurotransmitter metabolism at the blood-brain barrier
血脑屏障内皮单胺神经递质代谢
基本信息
- 批准号:10707495
- 负责人:
- 金额:$ 39.5万
- 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:2022-09-20 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlzheimer&aposs DiseaseAmino AcidsAmygdaloid structureAnxietyBehaviorBloodBlood - brain barrier anatomyBlood VesselsBlood brain barrier dysfunctionBrainBrain regionCellsCentral Nervous SystemChromosome MappingCommunitiesCuesDOPA decarboxylaseDarknessDataDopamineDopamine AgonistsDopamine AntagonistsDopamine ReceptorEndothelial CellsEndotheliumEnzymesEpilepsyFunctional disorderGenesGeneticGenetic TranscriptionGlucoseHaloperidolHealthHigh Pressure Liquid ChromatographyHormonesHousingImmunologic SurveillanceIonsKnock-outKnockout MiceLateralLeadLearningLightLinkMeasuresMetabolicMetabolic PathwayMetabolismModelingMonoamine OxidaseMoodsMovementMultiple SclerosisMusNeurodevelopmental DisorderNeuromodulatorNeuronsNeurophysiology - biologic functionNeurotransmittersNutrientPain DisorderParkinson DiseasePhenotypePost-Translational Protein ProcessingProcessPropertyProteinsRegulationRewardsSerotoninSignal TransductionSignaling MoleculeSocial BehaviorSocial InteractionSocial isolationStimulusStrokeSynapsesSystemTestingTight JunctionsTissuesToxinVascular Endothelial Cellantagonistapproach behaviorbehavioral responseblood-brain barrier functionbrain endothelial cellbrain tissueexperienceextracellularhabituationliquid chromatography mass spectrometrymonoaminemouse modelnervous system disorderneuralneural circuitneuropsychiatric disorderneurotransmitter metabolismnovelpainful neuropathypathogenresponseropinirolesensory stimulussocialspatial memorysynaptic functiontranscytosisuptake
项目摘要
The term blood-brain barrier collectively describes the properties of central nervous system (CNS) vasculature
which stringently regulate the movement of ions, molecules and cells between the blood and neural tissue. These
properties protect the CNS from toxins, pathogens and CNS immune surveillance, and provide the neural tissue
the necessary nutrients for proper function. The vascular endothelial cells of the CNS confer many of the
properties of the blood-brain barrier, they form paracellular and transcellular barriers, and possess distinct
transport properties that efflux potential toxins and deliver nutrients. Blood-brain barrier dysfunction is observed
in a wide array of neurological diseases including epilepsy, multiple sclerosis, stroke, Parkinson’s Disease and
Alzheimer’s Disease. The objective of this study is to identify novel genes that allow the blood-brain barrier to
regulate the health and function of the CNS. We identified several genes highly enriched in CNS endothelial cells
which are involved in the synthesis and degradation of monoamine neurotransmitters, dopamine and serotonin.
Dopamine and serotonin are neuromodulators as they potentiate the firing rate of neurons. Outside of the
synapse they function as traditional extracellular signaling molecules and hormones. Neural circuits incorporating
dopamine and serotonin are involved in learning, reward, movement and mood, while dysfunction in
monoaminergic systems are observed in a host of neurological diseases including Parkinson’s Disease,
Alzheimer’s Disease, neuropathic pain and neuropsychiatric disorders. Metabolism of dopamine and serotonin
by brain endothelial cells could be involved in the many processes and behaviors regulated by these monoamine
neurotransmitters. To determine the functions of blood-brain barrier monoamine neurotransmitter metabolism,
we generated conditional endothelial-specific knockouts of Ddc, MaoA and MaoB and examined the requirement
of these genes in behavior and the brain levels of dopamine and serotonin. Our preliminary studies suggest that
blood-brain barrier monoamine metabolism regulates the levels of monoamines in a behavior context-dependent
manner. We will use the conditional endothelial-specific knockout mouse models to examine how the blood-brain
barrier regulates behavior responses to sensory stimuli and determine the mechanisms by which blood-brain
barrier monoamine metabolism regulates monoamine neurotransmitter levels and behavior. Lastly, we will
examine if brain monoamine signaling is altered in endothelial-specific knockouts of blood-brain barrier
monoamine metabolic genes.
术语血脑屏障共同描述了中枢神经系统(CNS)血管系统的特性
它严格地调节血液和神经组织之间的离子、分子和细胞的运动。这些
保护中枢神经系统免受毒素、病原体和中枢神经系统免疫监视,
中枢神经系统的血管内皮细胞提供了许多必需的营养物质,
由于具有血脑屏障的特性,它们形成细胞旁和跨细胞屏障,并具有不同的
具有排出潜在毒素和输送营养物质的转运特性。
在广泛的神经系统疾病,包括癫痫,多发性硬化症,中风,帕金森病和
这项研究的目的是确定新的基因,使血脑屏障,
调节中枢神经系统的健康和功能。我们鉴定了几个在中枢神经系统内皮细胞中高度富集的基因
其参与单胺神经递质、多巴胺和血清素的合成和降解。
多巴胺和血清素是神经调质,因为它们增强神经元的放电率。
它们作为传统的细胞外信号分子和激素发挥作用。
多巴胺和5-羟色胺与学习、奖励、运动和情绪有关,而
单胺能系统在许多神经系统疾病中被观察到,
阿尔茨海默病、神经病理性疼痛和神经精神障碍。多巴胺和5-羟色胺的代谢
脑血管内皮细胞对这些单胺递质的依赖性可能参与这些单胺递质调节的许多过程和行为
为了确定血脑屏障单胺神经递质代谢的功能,
我们产生了Ddc、MaoA和MaoB的条件性内皮细胞特异性敲除,
这些基因在行为中的作用以及大脑中多巴胺和血清素的水平。我们的初步研究表明,
血脑屏障单胺代谢调节单胺水平的行为环境依赖性
我们将使用条件性内皮细胞特异性敲除小鼠模型来研究血脑屏障是如何被激活的。
屏障调节对感觉刺激的行为反应,并决定血脑屏障的机制。
屏障单胺代谢调节单胺神经递质水平和行为。最后,我们将
检查在内皮细胞特异性敲除血脑屏障中脑单胺信号是否改变
单胺代谢基因
项目成果
期刊论文数量(0)
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Roeben Munji其他文献
Roeben Munji的其他文献
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{{ truncateString('Roeben Munji', 18)}}的其他基金
Endothelial monoamine neurotransmitter metabolism at the blood-brain barrier
血脑屏障内皮单胺神经递质代谢
- 批准号:
10586780 - 财政年份:2022
- 资助金额:
$ 39.5万 - 项目类别:
Regulation of spinal cord development and the Wnt signaling pathway by Oto
Oto 调控脊髓发育和 Wnt 信号通路
- 批准号:
7485692 - 财政年份:2007
- 资助金额:
$ 39.5万 - 项目类别:
Regulation of spinal cord development and the Wnt signaling pathway by Oto
Oto 调控脊髓发育和 Wnt 信号通路
- 批准号:
7678362 - 财政年份:2007
- 资助金额:
$ 39.5万 - 项目类别:
Regulation of spinal cord development and the Wnt signaling pathway by Oto
Oto 调控脊髓发育和 Wnt 信号通路
- 批准号:
7328890 - 财政年份:2007
- 资助金额:
$ 39.5万 - 项目类别: