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

• 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
• 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

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 母亲的营养对胎儿和婴儿的大脑发育起着不可或缺的作用。因此，委员会认为， 在这一关键时期的营养缺乏会导致神经发育障碍。然而， 营养素对控制神经发育的细胞和分子机制的贡献在很大程度上是未知的。 二十二碳六烯酸（DHA），一种从多脂鱼中摄取的ω-3多不饱和脂肪酸（n-3 PUFA）， 在细胞膜的磷脂中积累，是大脑生长和成熟所必需的。虽然 DHA可以生物合成，后代主要依靠母亲的DHA来满足他们的需求。重要的是，全球 向西式饮食的转变也导致DHA摄入量减少，引起了人们对 对后代神经发育的影响。 DHA水平低的人表现出白色物质缺陷以及认知和行为缺陷。 此外，缺乏DHA的动物表现出来自小胶质细胞的促炎反应，小胶质细胞是大脑的常驻细胞。 免疫细胞小胶质细胞还调节髓鞘的发育和消除，髓鞘是轴突绝缘体， 增加神经冲动的速度并赋予白色物质颜色。事实上，我们实验室的新工作 表明小胶质细胞在正常发育过程中吞噬过量的髓鞘。然而，目前尚不清楚是否 低DHA状态的神经炎症和小胶质细胞后果最终导致 髓鞘形成 使用斑马鱼模型，我将通过遗传和母体饮食策略产生DHA耗尽的后代。 通过采用强大的单细胞转录组学和体内成像技术，我将研究是否低水平的转录组学。 DHA状态改变：小胶质细胞中炎症信号和吞噬相关基因表达（Aim 1）;髓鞘 发育和形态学（目标2）;和髓鞘的小胶质细胞吞噬作用（目标3）。这项工作 可以揭示低DHA状态导致白色物质缺陷的细胞机制， 优化婴儿健康和预防神经发育障碍的营养策略。 通过我在科罗拉多大学安舒茨医学院的培训，我将获得 概念，技术和必要的专业技能，以建立我的独立研究利基在 营养学和发育神经生物学的交叉。