Synthetic and Biological Studies of Chondroitin Sulfate Oligosaccharides and Glycopeptides

硫酸软骨素低聚糖和糖肽的合成及生物学研究

• 批准号: 1507226
• 负责人: Xuefei Huang
• 金额: $ 54万
• 依托单位: Michigan State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1507226&HistoricalAwards=false
• 关键词: Synthetic; Biological; Studies; Chondroitin; Sulfate

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Xuefei Huang from Michigan State University to study the synthesis and functions of chondroitin sulfate (CS) and chondroitin sulfate proteoglycans (CSPG). Carbohydrates play important roles in many biological processes. However, due to the lack of uniformity of complex carbohydrate structures in nature, it has been very challenging to thoroughly understand their function. This project will focus on one specific class of carbohydrates referred to as chondroitin sulfate (CS) and chondroitin sulfate proteoglycans (CSPG), chondroitin sulfate that is bonded to protein. New synthetic approaches will be developed to produce these complex molecules, which will greatly expand the range of structures that can be accessed through chemical synthesis. With these materials, it will be possible to establish the impact of different structures on the interactions of CS and CSPG with, for example, amyloid beta peptide, the precursor to the aggregates and plaques that are present in the brains of people with Alzheimer's disease. In addition, the engagement of graduate, undergraduate and high school researchers in this project will provide them with opportunities to be trained in the important and challenging field of complex carbohydrate synthesis. The results generated will provide a highlight for the power of synthetic chemistry, and how chemical synthesis can be utilized to address important biological problems. Chondroitin sulfate (CS) and chondroitin sulfate proteoglycans (CSPG) are involved in many important biological events including neural development, organ morphogenesis, inflammation, infection and beta amyloid plaque formation. The number and location of O-sulfates in CS and CSPG can significantly influence their biological properties. As naturally existing CS and CSPG contain heterogeneous sulfation patterns, it is highly challenging to decipher the detailed structure function relationship using CS and CSPG isolated from nature. Contradicting results have been reported in the literature. In order to overcome this problem and facilitate biological studies, synthetic methodologies will be developed to produce CS oligosaccharides and CSPG glycopeptides with well-defined sulfation patterns and structures. The utility of these compounds will be demonstrated in the study of CS/CSPG interactions with beta-amyloid peptide to investigate a potential mechanism for the formation of amyloid plaques, a pathological hallmark of Alzheimer's disease.

有了这个奖项，化学部的生命过程化学项目正在资助密歇根州立大学的黄雪飞博士研究硫酸软骨素（CS）和硫酸软骨素蛋白聚糖（CSPG）的合成和功能。碳水化合物在许多生物过程中起着重要作用。然而，由于自然界中复杂的碳水化合物结构缺乏统一性，彻底了解它们的功能一直是非常具有挑战性的。该项目将重点关注一类特定的碳水化合物，称为硫酸软骨素（CS）和硫酸软骨素蛋白聚糖（CSPG），即与蛋白质结合的硫酸软骨素。将开发新的合成方法来生产这些复杂的分子，这将大大扩大可以通过化学合成获得的结构范围。有了这些材料，将有可能建立不同结构对CS和CSPG与例如淀粉样β肽（存在于阿尔茨海默病患者大脑中的聚集体和斑块的前体）的相互作用的影响。此外，研究生、本科生和高中研究人员参与该项目将为他们提供在复杂碳水化合物合成这一重要而具有挑战性的领域接受培训的机会。所产生的结果将为合成化学的力量提供一个亮点，以及如何利用化学合成来解决重要的生物学问题。硫酸软骨素（CS）和硫酸软骨素蛋白聚糖（CSPG）参与许多重要的生物学事件，包括神经发育、器官形态发生、炎症、感染和β淀粉样蛋白斑块形成。CS和CSPG中O-硫酸盐的数量和位置可以显着影响其生物学特性。由于天然存在的CS和CSPG含有异质的硫酸化模式，因此使用从自然界分离的CS和CSPG来破译详细的结构功能关系是非常具有挑战性的。文献中报告了相互矛盾的结果。为了克服这个问题，促进生物学研究，将开发合成方法来生产CS寡糖和CSPG糖肽，具有明确的硫酸化模式和结构。这些化合物的效用将在CS/CSPG与β-淀粉样肽相互作用的研究中得到证实，以研究淀粉样斑块形成的潜在机制，淀粉样斑块是阿尔茨海默病的病理标志。