Studies on the Synthesis and Biochemistry of Complex Glycans

碳水化合物（也称为聚糖）在许多生物过程中起着关键作用。在过去的20年里，我的实验室一直专注于合成基于聚糖的探针，以在分子水平上建立对这些角色的理解。我们对微生物表面的聚糖特别感兴趣：细菌，真菌，寄生虫和病毒。我们的工作产生了双重影响，提供了合成聚糖的新方法，并产生了新的分子，这些分子被我的团队和合作者用于基础结构-功能研究。在这次发现补助金更新中，我们将工作扩展到三个新项目。选择用于研究的系统将联合收割机结构上有趣的分子与尚未看到实质性研究的系统和分子结合起来。这里提出的开创性研究将影响合成碳水化合物化学和微生物糖生物学领域。这三个项目将获得资助：*1。寄生虫和病毒中含有高度分支单糖残基的聚糖的合成。这些聚糖尚未成为合成研究的主题。除了揭示组装这些复杂结构的“规则”外，这项工作还将为我实验室的免疫化学研究和生物合成的合作研究提供探针。这项工作的长期应用包括病毒和寄生虫感染的新型疫苗或诊断，以及治疗病毒性疾病的化合物。2.结核分枝杆菌多糖的合成及其作为阿拉伯聚糖酶底物的评价。这些酶参与降解称为阿拉伯聚糖的分枝杆菌关键碳水化合物。这项工作将导致新的底物和这些酶的测定，这是潜在的目标，为新类别的抗分枝杆菌剂。3.与猪链球菌中发现的多糖相关的聚糖的合成，猪链球菌是养猪业的昂贵病原体，也是日益导致人类感染的生物体。这些S.以前没有得到合成化学家关注的猪聚糖将与合作者一起用于基础免疫学研究。一个长期目标是为动物和人类设计有效的疫苗和诊断测试。** 计划中的项目每年将培养6名研究生和1名本科生。所有学员将获得合成化学和有机分子表征的技能。在一些项目中，他们将获得检测开发或免疫学方面的专业技能（在我的小组或与合作者）。他们将在一个环境中工作，该环境在自然科学和工程领域的职业培训方面非常成功，将研究培训与针对每个人职业目标的专业发展机会相结合。

Carbohydrates (also called glycans) play pivotal roles in many biological processes. Over the past 20 years my lab has focused on synthesizing glycan-based probes to build understanding of these roles at the molecular level. We have been particularly interested in glycans that coat the surfaces of microbes: bacteria, fungi, parasites and viruses. Our work has had double impact, providing new methods to synthesize glycans and generating novel molecules that are used in fundamental structure–function studies both by my group and with collaborators. In this Discovery Grant renewal, we extend our work to three new projects. The systems chosen for study combine structurally intriguing molecules with systems and molecules that have not yet seen substantial investigation. The groundbreaking studies proposed here will impact the fields of synthetic carbohydrate chemistry and microbial glycobiology. The three projects to be supported by this grant are: ******1. Synthesis of glycans containing highly-branched monosaccharide residues that are found in parasites and viruses. These glycans have not yet been the subject of synthetic investigations. In addition to uncovering the ‘rules' for assembling these complex structures, this work will provide probes for immunochemical studies in my lab and collaborative studies on biosynthesis. Long-term applications of this work include novel vaccines or diagnostics for viral and parasitic infections, and compounds for treating viral diseases. ******2. Synthesis of glycans from the organism that causes tuberculosis, Mycobacterium tuberculosis, and their evaluation as substrates for arabinanases. These enzymes are involved in degrading key mycobacterial carbohydrates called arabinans. This work will lead to novel substrates and assays for these enzymes, which are potential targets for new classes of anti-mycobacterial agents. ******3. Synthesis of glycans related to polysaccharides found in Streptococcus suis, a costly pathogen for the pig industry and an organism that increasingly leads to human infections. These S. suis glycans, which have not previously received the attention of synthetic chemists, will be used in fundamental immunological studies with collaborators. A long-term goal is to design effective vaccines and diagnostic tests for these infections, both for animals and humans. ******The planned projects will train six graduate students and one undergraduate each year. All trainees will gain skills in synthetic chemistry and characterization of organic molecules. In some projects, they will gain specialized skills in assay development or immunology (in my group or with collaborators). They will work in an environment that has been highly successful in training individuals for careers in the natural sciences and engineering, by combining research training with professional development opportunities tailored to each individual's career objectives.