RUI: Protein Bioconjugation Strategies for Next Generation Silk Biomaterials

摘要：家蚕的蚕茧是由一种叫做丝素蛋白的蛋白质制成的。近年来，丝绸已成为最受欢迎的生物医学材料之一，应用范围从药物输送到制造人造组织。本文描述的蛋白质修饰策略的成功开发将为研究人员设计下一代具有增强性能和与生物系统集成的创新、功能性丝基生物材料铺平道路。在西华盛顿大学化学系，我们的核心任务是为本科生提供重要的，深入的研究机会。拟开展的研究项目将涉及约10-12名本科生和2-3名硕士。在为期三年的资助期内，资助5名学生。鉴于社区大学为许多弱势群体提供了接受高等教育的重要途径，这项拨款将为当地社区大学的学生每年夏天提供一笔额外的研究津贴。总的来说，这项工作将为学生在stem相关职业中取得成功所需的技能打下坚实的基础，将促进世界海洋大学内外教师之间的进一步合作，并将继续建立世界海洋大学与当地社区学院之间的关系。技术摘要：家蚕（Bombyx mori）生产的蚕丝已成为用途最广泛的生物材料之一，应用范围从工程组织、药物输送到光学和电子设备。对蚕丝蛋白的化学修饰为进一步定制蚕丝与生物系统之间的相互作用提供了机会，并赋予蚕丝新的功能。考虑到以前使用的生物偶联方法在选择性和官能团耐受性方面的局限性，需要互补化学来修饰丝绸，特别是在温和的水条件下发生的生物正交反应。为此，本工作的主要目标是通过1)氨基酪氨酸修饰策略和2)钯催化的交叉偶联反应，开发新的方法来化学修饰丝绸中异常高数量的酪氨酸残基。虽然这里开发的方法可以广泛应用，但我们将重点关注在体外和体内成像应用和靶向药物递送方面有价值的丝衍生物。总的来说，这项工作包括对丝蛋白反应性的基础探索，进一步努力将传统的有机反应转化为水环境，最终将产生新的蛋白质生物偶联方法，可应用于丝和其他含酪氨酸的蛋白质。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Non-technical Abstract:Bombyx mori silkworms produce cocoons made of a fascinating protein called silk fibroin. In recent years, silk has become one of the most popular biomedical materials for applications ranging from drug delivery to creating artificial tissues. Successful development of the protein modification strategies described here will pave the way for researchers to design the next generation of innovative, functional silk-based biomaterials with enhanced performance and integration with biological systems. In the Department of Chemistry at Western Washington University, our core mission is to provide undergraduate students with significant, in-depth research opportunities. The proposed research program will involve a total of ~10-12 undergraduates and 2-3 master?s students over the three-year grant period. Recognizing that community colleges offer critical access to higher education for many underrepresented groups, this grant will provide one additional research stipend per summer for a local community college student. Overall, this work will give students a strong foundation in the skills required to be successful in STEM-related careers, will foster further collaborations between faculty both within and outside of WWU, and will continue to build relationships between WWU and local community colleges. Technical Abstract: Silk produced by the Bombyx mori silkworm has emerged as one of the most versatile biomaterials for applications ranging from engineered tissues, to drug delivery, to optical and electronic devices. Chemical modification of the silk protein provides an opportunity to further customize the interaction between silk and living systems, and endow silk with new functionality. Given the limitations in selectivity and functional group tolerance of previously employed bioconjugation methods, there is a need for complementary chemistries for silk modification, particularly bio-orthogonal reactions that occur under mild, aqueous conditions. To this end, the primary goal of this work is to develop new methods to chemically-modify the unusually high number of tyrosine residues in silk by employing 1) amino tyrosine modification strategies and 2) palladium-catalyzed cross-coupling reactions. While the methods developed here can be broadly applied, we will focus on silk derivatives that will be valuable for in vitro and in vivo imaging applications and targeted drug delivery. Overall, this work involves fundamental explorations of silk protein reactivity, furthers efforts to translate traditional organic reactions into aqueous environments, and ultimately will result in new protein bioconjugation methods that can be applied to silk and other tyrosine-containing proteins.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.