Development and Application of Surface-Tethered Iterative Carbohydrate Synthesis

描述(申请人提供)：复杂的碳水化合物涉及广泛的生物现象，特别是它们在疾病过程中的参与，使这类天然化合物具有巨大的诊断和治疗潜力。为此，Pi‘s和co-Pi的实验室将他们的研究重点放在与碳水化合物相关的疾病上，这些疾病是全球十大主要死亡原因之一，即癌症、肺炎球菌病、败血症和阿尔茨海默病。这项工作的核心是相信，如果对这些碳水化合物的结构、构象和性质有全面的了解，就可能有助于阐明这些疾病的发病机制。因此，这可能导致开发有效的工具来预防、诊断和/或治疗这些疾病。PI和Co-PI研究计划的长期目标是使普通化学、生物化学、医学和工业受众更容易获得复杂碳水化合物，从而与糖生物学和相关健康科学的爆炸性领域保持同步。在此建议扩大我们实验室开始的研究，以开发用于低聚糖和糖共轭合成的高通量新技术。这项提议的核心是开发一种新的支持合成策略，称为STICS(表面拴系迭代碳水化合物合成)。拟议研究的学术价值在于它在成功完成后对基础和应用合成碳水化合物、表面和纳米材料化学领域做出了重大贡献。准确地说，这一努力的成功不仅将推动上述化学领域的发展，而且还将从根本上促进糖和纳米技术的进一步发展。我们相信，拟议的发展将导致发现新的方法，有效地合成和高通量筛选基于碳水化合物的文库和治疗药物。这项工作的一个更广泛和长期的影响涉及到本科生、研究生和博士后研究参与者将接受的表面、制备有机、碳水化合物、生物有机和材料化学方面的专业培训。此外，拟议研究的多学科性质将使学生能够在智力和实践意义上扩大他们的科学基础。在他们的实验室经验中，他们将学习重要的工具，通过开发新的方法和参与最先进的多步合成来获得、修改和分析有机分子和纳米材料。学生研究人员还将通过编写手稿和参加专业会议融入科学界。因此，学生将在接触科学话语的同时培养更好的沟通技能。最后，拟议的研究最终将加强与生物医学研究人员的跨学科合作。 与公共健康相关：拟议中的研究将通过开发一种新的碳水化合物合成策略来造福人类健康，该策略对诊断和治疗包括癌症和自身免疫性疾病在内的疾病以及开发基于干细胞的新疗法具有重要意义。表面支持碳水化合物合成的新技术将使这些分子更容易用于生物学研究，从而可能导致治疗剂的开发。我们用于支持合成的新方法所使用的纳米材料也可以用于诊断分析和干细胞生物学分类应用，使用作为该项目一部分的碳水化合物。

DESCRIPTION (provided by applicant): Complex carbohydrates are involved in a broad variety of biological phenomena and their involvement in disease processes, in particular, have given this class of natural compounds a tremendous diagnostic and therapeutic potential. To this end, the PI's and co-PI's laboratories have focused their research efforts towards carbohydrates associated with diseases that rank among the top 10 leading causes of death worldwide, i.e. cancer, pneumococcal disease, septicemia, and Alzheimer's disease. At the core of this effort is the belief that if a comprehensive knowledge of the structure, conformation, and properties of these carbohydrates were available, elucidation of the mechanisms for the pathogenesis of these diseases could be facilitated. Consequently, this could lead to the development of effective tools for the prevention, diagnosis, and/or treatment of these diseases. The long-term goals of the PI's and co-PI's research programs are to make complex carbohydrates more accessible to general chemical, biochemical, medical and industrial audiences, and thereby keep pace with the exploding areas of glycobiology and related health sciences. Proposed herein is the expansion of studies initiated in our laboratories for the development of novel high-throughput technologies for oligosaccharide and glycoconjugate synthesis. At the core of this proposal is the development of a new strategy for supported synthesis called STICS (Surface-Tethered Iterative Carbohydrate Synthesis). The intellectual merit of the proposed research lies in its significant contributions to the field of basic and applied synthetic carbohydrate, surface, and nanomaterial chemistries upon its successful completion. Precisely, the success of this endeavor will not only advance the field of chemistries mentioned, but also fundamentally contribute to further development of glyco- and nanotechnology in general. We trust that the proposed developments will lead to the discovery of novel methodologies for the efficient synthesis and high throughput screening of carbohydrate-based libraries and therapeutics. A broader and long-term impact of this work relate to the professional training in surface, preparative organic, carbohydrate, bioorganic, and materials chemistry that undergraduate, graduate and post-doctoral research participants will receive. In addition, the multidisciplinary nature of the proposed research will allow students to expand their scientific base in an intellectual and practical sense. During their laboratory experience they will learn important tools that allow obtain, modify, and analyze organic molecules and nanomaterials by means of developing new methodologies and participating in the elaboration of state-of-the-art, multi-step syntheses. Student researchers will also become integrated into the scientific community through the preparation of manuscripts and attendance at professional meetings. As a consequence, students will develop better communication skills while also being exposed to scientific discourse. Finally, the proposed research will ultimately strengthen interdisciplinary collaborations with biomedical researchers. PUBLIC HEALTH RELEVANCE: The proposed research will benefit human health by developing a new strategy for synthesizing carbohydrates significant in diagnosing and treating diseases including cancer and autoimmune diseases, and in the development of new therapies based on stem cells. The new technology for surface supported carbohydrate synthesis will result in these molecules becoming more accessible for biological studies that can lead to development of therapeutic agents. The nanomaterials used for our new approach to supported syntheses can also be used for diagnostic assays and stem cell biology sorting applications using the carbohydrates made as a part of this project.