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

项目描述（申请人提供）：本项目将重点研究硫酸软骨素（CS）糖胺聚糖，这是一类在发育、病毒侵袭、癌症和脊髓损伤中起重要作用的多糖。CS多糖在体内表现出不同的磺化模式，这些模式在时空上受到调节。然而，由于CS的结构复杂性和缺乏工具，鉴定特定硫酸基序功能的努力受到了阻碍。例如，定义明确的CS分子不能从天然来源中纯化，因此，该领域仅限于处理非均质硫酸化物混合物。负责CS生物合成的硫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球变化，因此很难确定特定硫酸化基序的作用。在这项资助中，我们将结合有机化学和生物学的工具来克服这些挑战。我们将利用合成化学来组装已定义的CS结构（包括天然的和非自然的），以获得关于CS结构-功能关系的基本新信息。当结合生物化学、遗传学、细胞生物学和神经生物学的力量时，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一种独特的化学方法，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。

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.