Dissecting neuronal lipid metabolism

剖析神经元脂质代谢

• 批准号: 10605689
• 负责人: Thomas Robert Clandinin
• 金额: $ 43.29万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605689
• 关键词: Adult; Affect; Anabolism; Animals; Biological; Brain; Brain Diseases; Calcium; Catabolism; Cells; Coupled; Data; Defect; Development; Disease; Drosophila genus; Enzymes; Foundations; Future; Gaucher Disease; Gene Proteins; Genes; Genetic Transcription; Glucosylceramides; Glycosphingolipids; Health; Homeostasis; Human; Hydrolase; Impaired cognition; Impairment; Label; Life; Link; Lipids; Lysosomes; Maintenance; Membrane; Membrane Lipids; Metabolism; Modeling; Morphology; Mutation; Nature; Neurites; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropathy; Neurophysiology - biologic function; Organizational Change; Parkinson Disease; Pathway interactions; Phenotype; Photoreceptors; Population; Process; Production; Publishing; Recycling; Reporter; Resolution; Retrieval; Role; Sleep; Sleep Deprivation; Sleep disturbances; Sorting - Cell Movement; Sphingolipids; Synapses; Synaptic Vesicles; Testing; Therapeutic; Therapeutic Intervention; Time; Transcriptional Regulation; Vesicle; Work; cell type; cellular targeting; disorder risk; enzyme substrate; fly; gene function; glucosylceramidase; in vivo; interest; lipid metabolism; lipidomics; mature animal; mind control; molecular targeted therapies; mutant; neuron development; novel therapeutics; optogenetics; perineural; prevent; proteostasis; relating to nervous system; sleep behavior; spatiotemporal; tool; transcription factor

Project Summary Dissecting neuronal lipid metabolism PI: Thomas R. Clandinin The brain is lipid rich, with the complexity of neural and glial membranes being fundamental to many aspects of neural function. To function appropriately, neural and glial membranes must maintain a cell-type appropriate composition of constituent lipids, and must continue to do so across adult life, even as ongoing vesicle fusion and retrieval make the control of lipid metabolism a fundamental challenge. At the same time, mutations that disrupt the biosynthesis and recycling of membrane lipids are associated with a large number of neurodegenerative diseases, making understanding how membrane lipids are produced, degraded, and recycled a problem of central interest. How is the lipid composition of specific cell types regulated in the adult brain, and how do alterations in lipid composition affect brain function in health and disease? This proposal focuses on the biosynthesis of glycosphingolipids, key constituents of neural and glial membranes that are evolutionarily conserved across metazoans, including humans. One of the genes involved in glycosphingolipid metabolism, Glucocerebrosidase (Gba) is associated with Parkinson’s Disease risk, as well as Gaucher Disease. However, how Gba acts in the adult brain remains incompletely understood. This proposal takes advantage of the evolutionarily conserved nature of Gba, using the fruit fly as a model to dissect the relative contributions of glia and neurons to Gba function. We focus specifically on two key questions. First, how is Gba function regulated by neural and glial activity? And second, how is Gba activity programmed during development, and transcriptionally regulated in adult neurons? These studies will broadly inform our understanding of how neural function is maintained across adult life, and dysregulated in neurodegenerative disease. As this understanding is fundamental to the development of novel drugs that modulate these pathways to prevent disease, these studies will broadly inform future therapeutic strategies.

项目摘要 神经细胞脂代谢的解剖 少年派：托马斯·R·克兰迪宁 大脑富含脂质，神经和神经胶质膜的复杂性是许多大脑的基础。 神经功能的各个方面。为了正常发挥功能，神经膜和神经胶质膜必须保持一种细胞类型 适当的组成脂质的组成，并且必须在成年后继续这样做，即使是在持续的情况下 囊泡融合和修复使脂代谢的控制成为一个根本性的挑战。同时， 破坏膜脂生物合成和循环的突变与大量 神经退行性疾病，了解膜脂是如何产生、降解和 循环利用了一个核心利益问题。成人体内特定细胞类型的脂质成分是如何调节的 在健康和疾病中，脂质成分的变化如何影响大脑功能？ 这项建议侧重于神经细胞和神经胶质的关键成分--神经鞘糖脂的生物合成。 包括人类在内的后生动物的膜在进化上是保守的。其中一个基因 参与神经鞘糖脂代谢的葡萄糖脑苷酶(GBA)与帕金森病有关 风险，以及高谢病。然而，GBA在成人大脑中的作用仍不完全清楚。 这一建议利用了GBA进化保守的性质，使用果蝇作为模型来 解剖神经胶质细胞和神经元对GBA功能的相对贡献。我们特别关注两个关键 问题。首先，GBA功能是如何受到神经和神经胶质活动的调节的？第二，GBA的活动如何 在发育过程中编程，并在成年神经元中进行转录调控？ 这些研究将广泛地帮助我们理解成年后神经功能是如何维持的。 生命，和神经退行性疾病的失调。因为这一认识是发展的基础 对于调节这些途径以预防疾病的新药，这些研究将广泛地告知未来 治疗策略。