CAREER: Glycoprotein mimetics with tailored galectin-binding properties based on self-assembled glycopeptide nanofibers

技术摘要：该奖项由材料研究部生物材料项目颁发，旨在合成和研究纳米纤维，模拟天然糖蛋白的结构、组成和功能，以调节半乳糖凝集素的生物活性。半乳糖凝集素是一种碳水化合物结合蛋白家族，在各种正常和病理过程中作为信号分子。所提出的纳米纤维是通过多肽的自组装制备的。纳米纤维碳水化合物的含量可以通过在预组装状态下以不同比例混合多肽和不含悬垂碳水化合物来改变。碳水化合物化学可以通过天然碳水化合物合成途径衍生的酶精确地改变组装后的结构。具有定制碳水化合物含量的纳米纤维将被用作研究半乳糖凝集素-糖蛋白相互作用的工具，这反过来将为设计新的治疗性生物材料提供信息，这些生物材料可以调节半乳糖凝集素的生物活性，用于各种应用，包括免疫治疗、癌症和病毒预防。这些研究工作将与外展工作相结合，为初中，高中和本科生提供动手工程经验，以激发他们对研究的兴趣，并为他们的STEM职业做好准备，特别强调吸引来自佛罗里达州北部代表性不足的社区的学生。通过这些经历，学生将培养重要的科学和领导技能，为他们独立的STEM职业生涯做好准备。非技术摘要本提案描述了创造可以调节凝集素活性的生物材料的研究，并可用于治疗各种疾病，包括自身免疫，癌症和病毒感染。在自然组织中，凝集素的活性是通过与附着在蛋白质或“糖蛋白”上的碳水化合物的相互作用来调节的。干扰半乳糖凝集素-糖蛋白相互作用的治疗方法常常受到碳水化合物合成困难和缺乏碳水化合物化学与半乳糖凝集素结合特异性之间明确定义的相关性的挑战。本研究将通过开发一种具有精确碳水化合物组成的纳米纤维的新方法来解决这些限制，然后使用这些纳米纤维来研究和定义半乳糖凝集素-糖蛋白的结合参数。反过来，这些参数将告知生物材料的设计，可以根据预期的治疗应用增强或抑制特定凝血素的活性。建议开展外展工作，以培养对STEM职业的早期兴趣，并通过大学教育持续下去。特别是，这些拓展工作将开发动手工程课程，向中学生介绍基本的工程概念，使一名高中生每年能够参加首席研究员实验室为期7周的全浸入式研究体验，并为本科生和研究生提供研究和指导机会。

Technical abstractThis award by the Biomaterials program in the Division of Materials Research proposes to synthesize and study nanofibers that mimic the structure, composition, and function of natural glycoproteins to modulate the biological activity of galectins, a family of carbohydrate-binding proteins that act as signaling molecules in various normal and pathological processes. The proposed nanofibers are fabricated via self- assembly of peptides. Nanofiber carbohydrate content can be varied by mixing peptides with and without a pendant carbohydrate at different ratios in the pre-assembled state. Carbohydrate chemistry can be precisely altered post-assembly via enzymes derived from natural carbohydrate synthesis pathways. Nanofibers with tailored carbohydrate content will be used as tools to study galectin-glycoprotein interactions, which in turn will inform design of new therapeutic biomaterials that can modulate galectin bioactivity for various applications, including immunotherapy, cancer, and viral prophylaxis. These research efforts will be coupled with outreach efforts that provide middle school, high school, and undergraduate students with hands-on engineering experiences to stimulate interest in research and prepare them for STEM careers, with a particular emphasis placed on attracting students from under- represented communities throughout northern Florida. Through these experiences, students will develop important scientific and leadership skills to prepare them for independent STEM careers.Non-technical abstractThis proposal describes research to create biomaterials that can modulate the activity of galectins, and could be useful in treating various conditions, including autoimmunity, cancer, and viral infection. Galectin activity is modulated in natural tissues via interactions with carbohydrates attached to proteins, or "glycoproteins". Efforts to create therapeutics that can interfere with galectin-glycoprotein interactions are often challenged by difficulties associated with carbohydrate synthesis and the lack of clearly defined correlations between carbohydrate chemistry and galectin binding specificity. This research will address these limitations by developing a new method to fabricate nanofibers with precise carbohydrate composition, and then using these nanofibers to study and define galectin-glycoprotein binding parameters. In turn, these parameters will inform the design of biomaterials that can enhance or inhibit activity of a particular galectin according to the intended therapeutic application. Outreach efforts are proposed to foster early interest in STEM careers that is sustained through collegiate education. In particular, these outreach efforts will develop hands-on engineering curricula to introduce middle school students to fundamental engineering concepts, enable one high school student per year to participate in a 7-week full-immersion research experience in the laboratory of the Principal Investigator, and provide undergraduate and graduate students with research and mentoring opportunities.