Role of n-3 polyunsaturated fatty acids in myelinationduring development

n-3 多不饱和脂肪酸在发育过程中髓鞘形成中的作用

基本信息

批准号：
10635282
负责人：
Katherine Marie Ranard
金额：
$ 6.95万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10635282
关键词：
Address Affect Anabolism Animals Automobile Driving Axon Behavioral Biological Models Biology Brain Cell Differentiation process Cell Lineage Cell membrane Cells Childhood Cognition Disorders Cognitive Color Colorado Consumption Defect Development Developmental Biology Docosahexaenoic Acids Docosahexaenoic acid supplementation Elements Exhibits Fishes Gene Expression Genes Genetic Growth Human Image Imaging Techniques Immune Immune response In Situ Hybridization Infant Infant Health Inflammatory Inflammatory Response Intake Knowledge Lactation Link Lipids Malnutrition Maternal Health Mediating Medical Mental disorders Microglia Modeling Molecular Mood Disorders Morphology Mothers Myelin Myelin Sheath N-3 polyunsaturated fatty acid Nerve Nervous System Neural tube Neurodevelopmental Deficit Neurodevelopmental Disorder Neurons Nutrient Nutritional Nutritional Requirements Nutritional Science Oligodendroglia Omega-3 Fatty Acids Patients Phagocytosis Phenotype Phospholipids Play Pregnancy Prevention strategy Process RNA Recovery Regulation Reporter Genes Research Role Signal Transduction Speed Synapses Techniques Testing Therapeutic Training Transgenic Organisms Universities Work Yolk Sac Zebrafish brain cell cognitive development cognitive function developmental neurobiology dietary dietary approach experimental study fetal genetic approach in vivo imaging insight molecular marker mother nutrition myelination neurobehavioral disorder neurodevelopment neuroinflammation novel nutrition offspring oligodendrocyte lineage oligodendrocyte precursor precursor cell prevent response skills tool transcriptome transcriptomics western diet white matter white matter injury

Address Affect Anabolism Animals Automobile Driving Axon Behavioral Biological Models Biology Brain Cell Differentiation process Cell Lineage Cell membrane Cells Childhood Cognition Disorders Cognitive Color Colorado Consumption Defect Development Developmental Biology Docosahexaenoic Acids Docosahexaenoic acid supplementation Elements Exhibits Fishes Gene Expression Genes Genetic Growth Human Image Imaging Techniques Immune Immune response In Situ Hybridization Infant Infant Health Inflammatory Inflammatory Response Intake Knowledge Lactation Link Lipids Malnutrition Maternal Health Mediating Medical Mental disorders Microglia Modeling Molecular Mood Disorders Morphology Mothers Myelin Myelin Sheath N-3 polyunsaturated fatty acid Nerve Nervous System Neural tube Neurodevelopmental Deficit Neurodevelopmental Disorder Neurons Nutrient Nutritional Nutritional Requirements Nutritional Science Oligodendroglia Omega-3 Fatty Acids Patients Phagocytosis Phenotype Phospholipids Play Pregnancy Prevention strategy Process RNA Recovery Regulation Reporter Genes Research Role Signal Transduction Speed Synapses Techniques Testing Therapeutic Training Transgenic Organisms Universities Work Yolk Sac Zebrafish brain cell cognitive development cognitive function developmental neurobiology dietary dietary approach experimental study fetal genetic approach in vivo imaging insight molecular marker mother nutrition myelination neurobehavioral disorder neurodevelopment neuroinflammation novel nutrition offspring oligodendrocyte lineage oligodendrocyte precursor precursor cell prevent response skills tool transcriptome transcriptomics western diet white matter white matter injury

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项目摘要

PROJECT SUMMARY Maternal nutrition plays an indispensable role in fetal and infant brain development. Accordingly, nutritional deficiencies during this critical window can cause neurodevelopmental disorders. Yet, exactly how nutrients contribute to the cellular and molecular mechanisms governing neurodevelopment is largely unknown. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (n-3 PUFA) consumed from fatty fish, accumulates in the phospholipids of cell membranes and is required for brain growth and maturation. Although DHA can be biosynthesized, offspring primarily rely on maternal DHA to meet their needs. Importantly, a global shift to Western-style diets has also led to decreased DHA intakes, raising concerns about the neurodevelopmental consequences for offspring. Humans with low DHA status display white matter defects and cognitive and behavioral deficits. Furthermore, DHA-deficient animals exhibit pro-inflammatory responses from microglia, the brain’s resident immune cells. Microglia also regulate the development and elimination of myelin, the axon insulator that increases the speed of nerve impulses and gives white matter its color. Indeed, novel work from our lab has shown that microglia phagocytose excess myelin during normal development. However, it is not known whether the neuroinflammatory and microglial consequences of low DHA status culminate in the abnormal regulation of myelination. Using a zebrafish model, I will generate DHA-depleted offspring via genetic and maternal diet strategies. By employing powerful single-cell transcriptomic and in vivo imaging techniques, I will investigate whether low DHA status alters: Inflammatory signaling and phagocytosis-related gene expression in microglia (Aim 1); myelin development and morphology (Aim 2); and the microglial phagocytosis of myelin sheaths (Aim 3). This work could reveal a cellular mechanism by which low DHA status leads to white matter defects and provide insight into nutritional strategies that optimize infant health and prevent neurodevelopmental disorders. Through my proposed training at the University of Colorado Anschutz Medical Campus, I will gain the conceptual, technical, and professional skills necessary to establish my independent research niche at the intersection of nutrition and developmental neurobiology.

项目摘要孕产妇营养在胎儿和婴儿脑发育中起着必不可少的作用。根据，在此关键窗口中的营养缺乏可能会导致神经发育障碍。但是，确切的方式营养有助于构成神经发育的细胞和分子机制。 Docosahexaenoic Acid（DHA），一种从脂肪鱼中消耗的omega-3多不饱和脂肪酸（N-3 PUFA），积聚在细胞膜的磷脂中，是大脑生长和成熟所必需的。虽然 DHA可以生物合成，后代主要依靠Mater DHA来满足他们的需求。重要的是，全球转向西方风格的饮食也导致DHA摄入量下降，引起了人们对后代的神经发育后果。 DHA状态低的人表现出白质缺陷以及认知和行为缺陷。此外，缺乏DHA的动物表现出小胶质细胞的促炎反应，大脑的居民免疫细胞。小胶质细胞还调节髓磷脂的发育和消除，即轴突绝缘子提高神经冲动的速度，并使白色物质的颜色。确实，我们实验室的新颖工作表明在正常发育过程中，小胶质细胞吞噬超过髓磷脂。但是，尚不知道是否低DHA状态的神经炎症和小胶质性后果在异常调节中的最终髓鞘。使用斑马鱼模型，我将通过遗传和孕产妇饮食策略产生DHA的后代。通过采用功能强大的单细胞转录组和体内成像技术，我将调查是否低 DHA状态改变：小胶质细胞中的炎症信号传导和与吞噬作用相关的基因表达（AIM 1）；髓线发展与形态学（AIM 2）；以及髓鞘鞘的小胶质细胞增多症（AIM 3）。这项工作可以揭示出低DHA状态导致白质缺陷并提供洞察力的细胞机制进入营养策略，以优化婴儿健康并预防神经发育障碍。通过我在科罗拉多大学安苏兹大学医学校园的拟议培训，我将获得在建立我的独立研究的概念，技术和专业技能上营养与发育神经生物学的交集。