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

描述(由申请人提供)：发展对神经元通讯基础的分子机制的理解，从而形成学习和记忆的基础，是现代科学的中心挑战之一。在这项提案中，重点是在这一过程中发挥核心作用的两种碳水化合物修饰，岩藻糖化和O-GlcNAc(O-连接N-乙酰氨基葡萄糖)糖基化。岩藻糖化蛋白在神经元突触中含量丰富，并与长期记忆巩固有关。O-GlcNAc糖基化是一种在神经元蛋白质上发现的动态的细胞内修饰，涉及基因表达、细胞信号和突触可塑性。我们工作的一个主要目标是了解这些糖影响神经元通讯和信息存储的分子机制。大脑中有哪些蛋白质被修饰，特定的碳水化合物是如何调节神经元蛋白质的结构和功能的？自然界使用碳水化合物结构编码功能信息的方式有没有共同的主题？解决这些问题对于理解碳水化合物的结构-活性关系及其在复杂大脑过程中的作用至关重要。由于我们的计划采用了化学方法，这项工作可能会揭示新的蛋白质和治疗干预途径，并帮助开发新的药物，旨在改善与衰老和神经退行性疾病相关的认知缺陷。与核酸和蛋白质不同，碳水化合物结构不是模板编码的，因此在体内检测和操作具有挑战性。因此，需要新的工具来补充生物化学和遗传学的传统方法，以促进我们对碳水化合物的理解。这项工作的重点是开发化学工具，以加快岩藻糖基和OGlcNAc糖及其相关蛋白质的发现和研究。当结合生物化学、遗传学和神经生物学的力量时，这些工具将为碳水化合物在神经系统中的生理作用提供新的见解，并揭示神经元通信、学习和记忆形成的新机制。这项工作的主要目标是了解碳水化合物如何有助于神经元交流的分子机制，从而形成学习和记忆的基础。最终，我们的研究应该揭示治疗干预的新靶点，并可能有助于开发新的药物来改善与衰老和神经退行性疾病相关的认知缺陷。

DESCRIPTION (provided by applicant): Developing an understanding of the molecular mechanisms that underlie neuronal communication, and hence form the basis of learning and memory, stands as one of the central challenges of modern science. In this proposal, the focus is on two carbohydrate modifications that play a central role in this process, fucosylation and O-GlcNAc (O-linked N-acetyglucosamine) glycosylation. Protein fucosylation is enriched at neuronal synapses and has been implicated in long-term memory consolidation. O-GlcNAc glycosylation is a dynamic, intracellular modification found on neuronal 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 these sugars influence neuronal communication and information storage. What proteins are modified in the brain, and how do specific carbohydrates regulate the structure and function of neuronal proteins? Are there common themes in the way Nature uses carbohydrate structures to encode functional information? Addressing these questions will be critical for understanding the structure-activity relationships of carbohydrates and their roles in complex brain processes. As our program takes a chemical approach, this work may reveal novel proteins and pathways for therapeutic intervention and aid in the development of new Pharmaceuticals designed to improve cognition deficits associated with aging and neurodegenerative disease. Unlike nucleic acids and proteins, carbohydrate structures are not template-encoded and thus are challenging to detect and manipulate in vivo. As such, new tools are needed to complement the traditional approaches of biochemistry and genetics to advance our understanding of carbohydrates. This work focuses on the development of chemical tools to accelerate the discovery and study of fucosyl and OGlcNAc sugars and their associated proteins. When combined with the power of biochemistry, genetics and neurobiology, these tools will provide new insights into the physiological roles of carbohydrates in the nervous system and uncover novel mechanisms of neuronal communication, learning and memory formation. The major goal of this work is to understand how carbohydrates contribute to the molecular mechanisms that underlie neuronal communication and hence form the basis of learning and memory. Ultimately, our studies should reveal novel targets for therapeutic intervention and may aid in developing new Pharmaceuticals for improving cognition deficits associated with aging and neurodegenerative disease.