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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：
10586780
负责人：
Roeben Munji
金额：
$ 39.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
https://reporter.nih.gov/project-details/10586780
关键词：
Affect Alzheimer&apos s Disease Amino Acids Amygdaloid structure Anxiety Behavior Blood Blood - brain barrier anatomy Blood Vessels Brain Brain region Cells Chromosome Mapping Communities Cues DOPA decarboxylase Data Dopamine Dopamine Agonists Dopamine Antagonists Endothelial Cells Endothelium Enzymes Epilepsy Functional disorder Genes Genetic Genetic Transcription Glucose Haloperidol Health High Pressure Liquid Chromatography Hormones Housing Immunologic Surveillance Ions Knock-out Knockout Mice Lateral Lead Learning Light Link Measures Metabolic Metabolic Pathway Metabolism Modeling Modification Monoamine Oxidase Moods Movement Multiple Sclerosis Mus Neuraxis Neurodevelopmental Disorder Neuromodulator Neurons Neurophysiology - biologic function Neurotransmitters Nutrient Pain Disorder Parkinson Disease Phenotype Process Property Proteins Regulation Rewards Serotonin Signal Transduction Signaling Molecule Social Behavior Social Interaction Social isolation Stimulus Stroke Synapses System Testing Tight Junctions Tissues Toxin Translations Vascular Endothelial Cell approach behavior behavioral response blood-brain barrier function brain endothelial cell brain tissue experience extracellular habituation liquid chromatography mass spectrometry monoamine mouse model nervous system disorder neural circuit neuropsychiatric disorder neurotransmitter metabolism novel painful neuropathy pathogen relating to nervous system response ropinirole sensory stimulus social spatial memory synaptic function transcytosis uptake

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.

血脑屏障这一术语统称为描述了中枢神经系统(CNS)和血管系统的重要特性。它严格地调节血液中的离子、分子和细胞在血液和神经组织之间的运动。保护中枢神经系统免受毒素、病原体和免疫系统监视的特性，以及为中枢神经系统提供免疫系统组织的特性。正常的神经功能需要必要的营养。中枢神经系统的血管内皮细胞和血管内皮细胞提供了许多功能。血脑屏障的性质可以形成跨细胞屏障和跨细胞屏障，它们具有截然不同的特点。运输特性表明，血液流出的是潜在的毒素，并提供营养物质。血脑屏障和功能障碍是观察到的。在中国，一系列常见的神经系统疾病，包括癫痫、多发性硬化症、中风、帕金森氏症等。阿尔茨海默氏病。这项研究的主要目标是进一步确定新的遗传基因，使人类的血脑屏障功能得以发挥作用。调节中枢神经系统的健康和功能。我们已经确定了几个在中枢神经系统内皮细胞中高度富含蛋白质的易感基因。它们也参与了单胺类神经递质、多巴胺和5-羟色胺的合成和降解过程。多巴胺和5-羟色胺是两种神经调节剂，因为它们可以增强神经元的放电频率。突触说，它们的功能类似于传统的细胞外信号转导分子和荷尔蒙。神经回路正在整合细胞外信号。多巴胺和5-羟色胺参与学习、奖赏、运动和情绪，而大脑功能障碍则与此有关。在包括帕金森氏症在内的多种神经系统疾病的宿主中，也观察到了单胺类神经系统。阿尔茨海默氏症、神经病理性疼痛和神经精神性精神障碍，以及多巴胺和5-羟色胺代谢障碍。通过大脑，内皮细胞可能也参与了许多神经过程和行为的调节，这些神经单胺类物质。神经递质。旨在确定血脑屏障和单胺类神经递质的主要功能。我们生成了DDC、MAOA和MAOB的有条件的内皮特异性基因敲除规则，并根据规则要求进行了审查。在这些基因中，有一些与行为有关，并影响了大脑中多巴胺和血清素的水平。我们的初步研究表明，这一点是正确的。血脑屏障和单胺类物质的代谢在一定程度上调节着单胺类物质的水平，这是一种与上下文相关的行为。方式。我们将不会使用新的有条件的内皮特异性基因敲除小鼠模型来进一步研究血液脑是如何变化的。屏障蛋白调节人的行为和对感官刺激的反应，并决定影响血液和大脑的免疫机制。单胺类神经代谢屏障调节单胺类神经递质水平和行为。最后，我们将继续努力。检查在血脑屏障的内皮特异性基因敲除过程中，大脑中的单胺类信号通路是否发生了变化。单胺与新陈代谢相关基因。