Role of Fucosyl Saccharides and O-GlcNAc Glycosylation in Neuronal Communication

岩藻糖基糖和 O-GlcNAc 糖基化在神经元通讯中的作用

• 批准号: 7846392
• 负责人: Linda C Hsieh-Wilson
• 金额: $ 48.29万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846392
• 关键词: Acetylglucosamine; Address; Age; Alzheimer' s Disease; Animal Model; Animals; Applications Grants; Arts; Behavior; Behavioral Paradigm; Biochemistry; Brain; Brain Injuries; CREB1 gene; Carbohydrates; Cells; Chemicals; Chemistry; Cognition; Cognitive deficits; Communication; Communications Media; Complement; Complex; DNA; Defect; Dendrites; Dendritic Spines; Detection; Development; Disease; Drosophila melanogaster; Drug Addiction; Electrophysiology (science); Enzymes; Epilepsy; Exhibits; Fluorescence Microscopy; Fragile X Syndrome; Fucose; Funding; Galactose; Gel; Gene Expression; Genetic; Genetically Engineered Mouse; Glycoproteins; Goals; Grant; Human; Image; Imagery; Infection; Inflammation; Information Storage; Ischemia; Label; Laboratories; Lead; Learning; Lectin; Life; Link; Long-Term Potentiation; Maps; Measures; Mediating; Memory; Memory impairment; Mental Retardation; Methodology; Methods; Modeling; Modification; Molecular; Molecular Target; Monitor; Morphology; Mus; Nature; Neoplasm Metastasis; Nerve; Neurobiology; Neurodegenerative Disorders; Neurons; O-GlcNAc transferase; Oximes; Pathway interactions; Pharmacologic Substance; Phosphorylation; Physiological; Physiology; Play; Post-Translational Protein Processing; Probability; Process; Property; Protein Biosynthesis; Proteins; Proteome; Proteomics; Recovery; Regulation; Rodent; Role; Science; Signal Pathway; Signal Transduction; Site; Slice; Structure; Structure-Activity Relationship; Synapses; Synapsin I; Synapsins; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; System; Time; United States National Institutes of Health; Up-Regulation; Work; aging brain; analog; base; carbohydrate structure; cognitive function; conditioned fear; cycloaddition; design; embryonic stem cell; glycosylation; human FRAP1 protein; improved; in vivo; insight; long term memory; morris water maze; neuron development; neuronal cell body; neuronal growth; neurotransmitter release; novel; novel therapeutics; pluripotency; postsynaptic; prepulse inhibition; protein structure function; public health relevance; relating to nervous system; response; self-renewal; small molecule; sugar; tool; trafficking; transcription factor

DESCRIPTION (provided by applicant): This revision application to 5R01 GM084724-06 has been submitted in response to Notice Number NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications." The application represents a significant expansion of the scope of the original project to investigate the role of O-GlcNAc (O-linked N-acetyglucosamine) glycosylation in learning and memory. Developing an understanding of the molecular mechanisms that underlie learning and memory stands as one of the central challenges of modern science. Our proposed studies will focus on a carbohydrate modification that plays a central role in this process: O-GlcNAc glycosylation. O-GlcNAc glycosylation is a dynamic, intracellular modification found on proteins involved in gene expression, cell signaling, and synaptic plasticity. A major goal of our work is to develop an understanding of the molecular mechanisms by which this sugar influences neuronal communication and information storage. Long-term memory is widely believed to occur through changes in synapse number and strength during learning. Such changes, termed "synaptic remodeling," require new protein synthesis in dendrites, the branched projections on the cell that conduct nerve impulses from the synapse to the cell body. Blockade of protein synthesis has been shown to inhibit learning and memory, demonstrating a direct functional link between dendritic protein synthesis, synaptic remodeling, and behavior. Recently, we made the exciting discovery that O-GlcNAc glycosylation is required for activity-dependent protein synthesis in dendrites. Here, we will investigate this discovery in greater mechanistic detail to understand how O-GlcNAc glycosylation regulates dendritic protein synthesis and its consequences for synaptic plasticity. In addition, we will probe whether elimination of O-GlcNAc glycosylation in the brain leads to learning and memory deficits in mice. A unique feature of this proposal is the seamless integration of chemistry with challenging neurobiological studies. We believe that the combination of cutting-edge chemical tools with state-of- the-art neurobiological approaches will be necessary to address the complex, fundamental question of how memories are stored. The proposed studies will significantly advance our understanding of the structure-activity relationships of carbohydrates in the brain and reveal new insights into the molecular basis of learning and memory. At the same time, our studies may ultimately impact the development of pharmaceuticals by revealing novel molecular targets and processes for the treatment of cognitive deficits associated with aging, brain injury, mental retardation, and neurodegenerative disease. PUBLIC HEALTH RELEVANCE: A major goal of this work is to elucidate molecular mechanisms that underlie neuronal communication and hence form the basis of learning and memory. Through the discovery of novel small molecules, proteins and pathways involved in neural communication and function, this work may aid ultimately in the development of new pharmaceuticals designed to improve cognition deficits associated with aging and neurodegenerative disease.

说明（由申请人提供）：针对 5R01 GM084724-06 的修订申请是为了响应编号 NOT-OD-09-058 的通知而提交的，标题为“NIH 宣布恢复法案资金用于竞争性修订申请的可用性”。该应用代表了原始项目范围的显着扩展，该项目旨在研究 O-GlcNAc（O-连接的 N-乙酰氨基葡萄糖）糖基化在学习和记忆中的作用。 了解学习和记忆背后的分子机制是现代科学的核心挑战之一。我们提出的研究将重点关注在此过程中发挥核心作用的碳水化合物修饰：O-GlcNAc 糖基化。 O-GlcNAc 糖基化是一种动态的细胞内修饰，存在于参与基因表达、细胞信号传导和突触可塑性的蛋白质上。我们工作的一个主要目标是了解这种糖影响神经元通讯和信息存储的分子机制。人们普遍认为，长期记忆是通过学习过程中突触数量和强度的变化而发生的。这种变化被称为“突触重塑”，需要在树突中合成新的蛋白质，树突是细胞上的分支投射，将神经冲动从突触传导到细胞体。蛋白质合成的阻断已被证明会抑制学习和记忆，证明树突蛋白合成、突触重塑和行为之间存在直接的功能联系。最近，我们有了令人兴奋的发现，O-GlcNAc 糖基化是树突中活性依赖性蛋白质合成所必需的。在这里，我们将更详细地研究这一发现，以了解 O-GlcNAc 糖基化如何调节树突蛋白合成及其对突触可塑性的影响。此外，我们将探讨大脑中 O-GlcNAc 糖基化的消除是否会导致小鼠的学习和记忆缺陷。 该提案的一个独特之处在于化学与具有挑战性的神经生物学研究的无缝结合。我们相信，尖端化学工具与最先进的神经生物学方法的结合对于解决记忆如何存储这一复杂而基本的问题是必要的。拟议的研究将显着增进我们对大脑中碳水化合物的结构-活动关系的理解，并揭示对学习和记忆的分子基础的新见解。与此同时，我们的研究可能通过揭示治疗与衰老、脑损伤、智力低下和神经退行性疾病相关的认知缺陷的新分子靶点和过程，最终影响药物的开发。 公共健康相关性：这项工作的一个主要目标是阐明神经元通讯的分子机制，从而构成学习和记忆的基础。通过发现涉及神经通讯和功能的新型小分子、蛋白质和通路，这项工作最终可能有助于开发旨在改善与衰老和神经退行性疾病相关的认知缺陷的新药物。