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

描述(由申请人提供)：此5R01 GM084724-06的修订申请是为了响应编号为NOT-OD-09-058的通知而提交的，通知编号为“NIH宣布恢复法案资金可用于竞争性修订申请”。这项申请代表着最初研究O-GlcNAc(O-连接N-乙酰氨基葡萄糖)糖基化在学习和记忆中的作用的项目范围的显著扩展。发展对构成学习和记忆基础的分子机制的理解是现代科学的核心挑战之一。我们建议的研究将集中在在这一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，长时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，需要树突中新的蛋白质合成，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。阻断蛋白质合成已被证明抑制学习和记忆，表明树突状蛋白质合成、突触重构和行为之间存在直接的功能联系。最近，我们有了一个令人兴奋的发现，O-GlcNAc糖基化是树突中活性依赖的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状蛋白的合成及其对突触可塑性的影响。此外，我们还将探讨大脑中O-GlcNAc糖基化的消除是否会导致小鼠的学习和记忆障碍。这一提议的一个独特特点是化学与具有挑战性的神经生物学研究的无缝结合。我们认为，将尖端化学工具与最先进的神经生物学方法相结合，将是解决记忆如何存储这一复杂的基本问题所必需的。拟议中的研究将极大地促进我们对大脑中碳水化合物结构-活性关系的理解，并揭示学习和记忆的分子基础的新见解。同时，我们的研究可能最终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的分子靶点和过程来影响药物的发展。 与公共健康相关：这项工作的一个主要目标是阐明神经元交流的分子机制，从而形成学习和记忆的基础。通过发现新的小分子、蛋白质和参与神经交流和功能的途径，这项工作可能最终有助于开发新的药物，旨在改善与衰老和神经退行性疾病相关的认知缺陷。

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.