A chemical approach to elucidating the structure-function relationships of chondr

描述（由申请人提供）：该项目将集中于硫酸软骨素（CS）糖胺聚糖，一类多糖，在发育，病毒入侵，癌症和脊髓损伤中发挥重要作用。CS多糖显示不同的硫酸化模式，在体内的时空调节。然而，由于CS的结构复杂性和缺乏工具，确定特定硫酸化基序功能的努力受到阻碍。例如，定义明确的CS分子不能从天然来源纯化，因此，该领域仅限于使用化合物的非均相硫酸化混合物。负责CS生物合成的磺基转移酶基因之一的遗传缺失可以在整个碳水化合物链中传播全局变化，使得难以确定特定硫酸化基序的作用。在这项资助中，我们将联合收割机有机化学和生物学的工具，以克服这些挑战。我们将利用合成化学来组装定义的CS结构（天然和非天然），以获得有关CS结构-功能关系的全新信息。当与生物化学，遗传学，细胞生物学和神经生物学的力量相结合时，这些分子将为碳水化合物在神经系统中的生理作用提供新的见解，并揭示神经元生长和修复的新机制。由于我们的项目采用了独特的化学方法，这项工作可能会揭示新的蛋白质和治疗干预途径，并有助于开发新的药物来刺激损伤，衰老或疾病后的再生。 公共卫生相关性：本研究旨在了解硫酸软骨素糖胺聚糖的结构如何调节基本的生物过程，如蛋白质识别和调节，细胞间通讯，发育和损伤后再生。通过发现这些过程中涉及的新的小分子、蛋白质和途径，这项工作可能最终有助于开发新的治疗方法来治疗各种疾病，如癌症、传染病和神经退行性疾病。

DESCRIPTION (provided by applicant): This project will focus on chondroitin sulfate (CS) glycosaminoglycans, a class of polysaccharides that play important roles in development, viral invasion, cancer, and spinal cord injury. CS polysaccharides display diverse sulfation patterns that are spatiotemporally regulated in vivo. However, efforts to identify functions for specific sulfation motifs have been hampered by the structural complexity of CS and a lack of tools. For instance, well-defined CS molecules cannot be purified from natural sources, and as a consequence, the field has been limited to working with heterogeneously sulfated mixtures of compounds. Genetic deletion of one of the sulfotransferase genes responsible for CS biosynthesis can propagate global changes throughout the carbohydrate chain, making it difficult to pinpoint the role of specific sulfation motifs. In this grant, we will combine the tools of organic chemistry and biology to overcome these challenges. We will exploit synthetic chemistry to assemble defined CS structures (both natural and non-natural) to obtain fundamentally new information about the structure- function relationships of CS. When combined with the power of biochemistry, genetics, cell biology, and neurobiology, these molecules will provide new insights into the physiological roles of carbohydrates in the nervous system and uncover novel mechanisms of neuronal growth and repair. As our project takes a distinctly chemical approach, this work may reveal novel proteins and pathways for therapeutic intervention and aid in the development of new pharmaceuticals to stimulate regeneration after injury, aging or disease. PUBLIC HEALTH RELEVANCE: This research seeks to understand how the structure of chondroitin sulfate glycosaminoglycans regulates fundamental biological processes, such as protein recognition and regulation, cell-cell communication, development, and regeneration after injury. Through the discovery of novel small molecules, proteins and pathways involved in these processes, this work may aid ultimately in the development of new therapeutic approaches to a broad range of disease states, such as cancer, infectious and neurodegenerative diseases.