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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：
10707495
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/10707495
关键词：
Affect Alzheimer&apos s Disease Amino Acids Amygdaloid structure Anxiety Behavior Blood Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Brain Brain region Cells Central Nervous System Chromosome Mapping Communities Cues DOPA decarboxylase Darkness Data Dopamine Dopamine Agonists Dopamine Antagonists Dopamine Receptor 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 Monoamine Oxidase Moods Movement Multiple Sclerosis Mus Neurodevelopmental Disorder Neuromodulator Neurons Neurophysiology - biologic function Neurotransmitters Nutrient Pain Disorder Parkinson Disease Phenotype Post-Translational Protein Processing 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 Vascular Endothelial Cell antagonist 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 neural circuit neuropsychiatric disorder neurotransmitter metabolism novel painful neuropathy pathogen 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.

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