Using Glycodendrimers to Elucidate the Importance of Multivalency in the Structures and Functions of Galectins

使用糖树聚合物阐明多价性在半乳糖凝集素结构和功能中的重要性

• 批准号: 2227874
• 负责人: Mary Cloninger
• 金额: $ 45万
• 依托单位: Montana State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2227874&HistoricalAwards=false
• 关键词: Using; Glycodendrimers; Elucidate; Importance; Multivalency

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Mary Cloninger from Montana State University to develop sugar-modified highly branched compounds to study the important roles that galectins play in cell-to-cell interactions. Galectins are carbohydrate binding proteins involved in many physiological functions that involve how cells interact and communicate with other cells and are linked to diseases such as fibrosis, cancer and heart disease. A set of highly branched molecules, called glycodendrimers, with varied numbers of sugars displayed on their surfaces will be synthesized. These glycodendrimers will be used in biochemical, structural, and cell biological studies to investigate the effects that carbohydrate binding has on how galectins interact with each other and how these protein interactions affect cell-to-cell interactions. Under this project, the PI will reach out to students from diverse populations to bring these students into the Cloninger research group through outreach programs with Flathead Valley Community College (FVCC) and local high schools. In addition, Dr. Cloninger and her undergraduate and graduate students will present their research to chemistry classes at four local high schools and give interested high school students opportunities to perform microscopy experiments at Montana State University.Although galectins play a critical role in cellular recognition processes through their binding interactions with cell surface carbohydrates, modulation of the interplay between their multivalent and monovalent functionalities is not well understood. Moreover, whether galectins from the three subfamilies have synergistic or distinct functions is currently unknown. The proposed research will use glycodendrimers to better understand galectin structure-function relationships. Lactose-functionalized glycodendrimers are ideal macromolecules with which to study multivalent carbohydrate-lectin interactions because both their size and the number of carbohydrate end groups can be systematically varied. Thus, glycodendrimers will be used to identify the role of the N-terminal domain in directing multivalent galectin-3/carbohydrate interactions. In addition, glycodendrimers will be used to evaluate whether galectins from the three subfamilies are working in concert to achieve increased specificity and selectivity in their multivalent interactions. Dynamic light scattering, transmission electron microscopy and fluorescence microscopy will be employed to visualize glycodendrimer-lectin interactions. In addition, cellular uptake, and cellular aggregation assays using a series of glycodendrimers binding to galectin-3 and to mixtures of galectins will be performed. Elucidating the key principles that guide multivalent interactions in complex environments is essential for understanding the role of multivalent associations between cell surface carbohydrates and galectins. In this regard, carbohydrate-functionalized dendrimers provide an ideal platform for the requisite systematic study of the role of multivalent interactions in carbohydrate-lectin binding.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

有了这个奖项，化学系的生命过程计划的化学资助教授玛丽Cloninger从蒙大拿州立大学开发糖修饰的高度分支的化合物，研究半乳糖凝集素在细胞间相互作用中发挥的重要作用。半乳糖凝集素是碳水化合物结合蛋白，参与许多生理功能，涉及细胞如何与其他细胞相互作用和交流，并与纤维化，癌症和心脏病等疾病有关。将合成一组高度分支的分子，称为糖树枝状聚合物，其表面显示不同数量的糖。这些glycodendrimer将用于生物化学，结构和细胞生物学研究，以研究碳水化合物结合对半乳糖凝集素相互作用的影响以及这些蛋白质相互作用如何影响细胞间相互作用。在这个项目下，PI将接触来自不同人群的学生，通过与平头谷社区学院（FVCC）和当地高中的外联计划，将这些学生带入Cloninger研究小组。此外，Cloninger博士和她的本科生和研究生将在当地四所高中的化学课上展示他们的研究，并让感兴趣的高中生有机会在蒙大拿州立大学进行显微镜实验。虽然半乳糖凝集素通过与细胞表面碳水化合物的结合相互作用在细胞识别过程中发挥着关键作用，它们的多价和单价官能团之间的相互作用的调节还没有被很好地理解。此外，来自三个亚家族的半乳糖凝集素是否具有协同或不同的功能目前尚不清楚。拟议的研究将使用glycodendrimers更好地了解半乳糖凝集素的结构与功能的关系。乳糖功能化的糖树枝状聚合物是研究多价碳水化合物-凝集素相互作用的理想大分子，因为它们的大小和碳水化合物末端基团的数量可以系统地变化。因此，glycodendrimer将用于确定N-末端结构域在指导多价半乳糖凝集素-3/碳水化合物相互作用中的作用。此外，glycodendrimers将用于评估来自三个亚家族的半乳糖凝集素是否协同工作，以实现其多价相互作用的特异性和选择性增加。动态光散射，透射电子显微镜和荧光显微镜将可视化glycodendrimer-lectin相互作用。此外，将使用一系列与半乳糖凝集素-3和半乳糖凝集素混合物结合的糖树枝状聚合物进行细胞摄取和细胞聚集测定。阐明在复杂环境中指导多价相互作用的关键原则对于理解细胞表面碳水化合物和半乳糖凝集素之间的多价关联的作用至关重要。 在这方面，碳水化合物官能化的树枝状聚合物提供了一个理想的平台，为必要的系统研究的作用，多价相互作用的碳水化合物-凝集素binding.This奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。