CAREER: Synthesis of Multiple Architectures of Decodable Biohybrid Polymer Libraries

职业：可解码生物杂化聚合物文库多种架构的合成

• 批准号: 2045021
• 负责人: Abigail Knight
• 金额: $ 69.75万
• 依托单位: University of North Carolina at Chapel Hill
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2045021&HistoricalAwards=false
• 关键词: CAREER; Synthesis; Multiple; Architectures; Decodable

Non-Technical Summary: Polymers are pervasive in society – from plastic bottles to fingerprint resistant coatings on cell-phone screens, these materials are a critical component of global technological, medical, and environmental advances. Despite this ubiquity, many polymers are currently designed and analyzed with only one specific application in mind. It can take years to identify an existing polymer that would be appropriate for use in a different application, especially if the chemical and physical properties required for the new application are unknown. To help match polymer materials to new applications, this proposal describes a synthetic platform that will enable hundreds of thousands of materials to be screened simultaneously – a scale orders of magnitude above current strategies for synthetic polymers and rivaling technologies like Nobel prize-winning directed evolution. To facilitate high throughput polymer screening, DNA will be used as a staple to bring together multiple polymer blocks. The modular assembly strategy allows for few synthetic pieces to lead to large libraries of hybrid block copolymers. The DNA staples have also been designed to carry identifying information that can help decode which polymer blocks have been stapled together, even in complicated mixtures. Once polymer blocks have been stapled together, the resulting hybrid materials can be screened for desirable properties (such as the ability to shield proteins from harsh environments, which is useful for stabilizing protein-based drugs like insulin), then isolated and identified using DNA sequencing strategies. This project requires interdisciplinary inspiration and techniques, which is an aspect of scientific achievements that is frequently overlooked in the classroom. To address this disconnect, two education programs building on current successful frameworks are proposed: (1) BioInspiring – on-site and virtual activities connecting biology-inspired science to every-day items and (2) Sci-athonU – a collaborative student competition to generate interdisciplinary research proposals that target global challenges. The objective of these educational programs is to increase access to STEM resources that highlight communication and collaboration as critical elements of science. This proposed research program has the long terms goals of revealing design principles for polymers with sophisticated functions to advance national medical, technological, and environmental goals, while providing novel approaches to increasing the motivation and retention of students from groups historically underrepresented in STEM. Technical Summary: Decodable polymer libraries have the potential to revolutionize the identification of structure-function relationships for synthetic macromolecules. While the protein data bank (PDB) contains structural information for almost 50,000 distinct proteins, there are significantly fewer characterized materials within the diverse structure space of synthetic macromolecules, leaving the identification of structure-function relationships in its infancy. High-throughput experimentation has had a revolutionary impact on biochemistry with RNA seq revealing real-time quantitation of protein expression and directed evolution yielding unique protein structure-function relationships. Despite the impact of these powerful combinatorial approaches, high-throughput experimentation with synthetic polymers remains rare. With current techniques, each polymer must be characterized in parallel, as there is currently no strategy for the rapid identification of polymers isolated from a mixture. Motivated by this fundamental gap, this work aims to use DNA “staples” that encode the polymer composition throughout a block copolymer and to provide proof-of-principle high-throughput assays characterizing polymer morphology and protein stabilization. Synthetic strategies are proposed for the design of linear, brush, and star-like polymer morphologies assembled with strategically designed architectures, and sequencing protocols are proposed to identify isolated polymers. The ultimate goal of this proposal is to provide a platform that expands the capabilities of polymer characterization from hundreds to thousands of polymers in a single experiment, enabling rapid identification of novel relationships between polymer structure and advanced functions.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.

非技术概述：聚合物在社会中无处不在--从塑料瓶到手机屏幕上的防指纹涂层，这些材料是全球技术、医疗和环境进步的关键组成部分。尽管这种无处不在，但目前许多聚合物的设计和分析只考虑到了一种特定的应用。确定一种适用于不同应用的现有聚合物可能需要数年时间，特别是在新应用所需的化学和物理性能未知的情况下。为了帮助将聚合物材料与新的应用相匹配，这项提案描述了一个合成平台，它将使数十万种材料能够同时进行筛选--这一规模比目前合成聚合物的战略和诺贝尔奖获得者定向进化等竞争技术高出一个数量级。为了促进高通量聚合物筛选，DNA将被用作将多个聚合物块连接在一起的订书针。模块化组装策略允许很少的合成片段形成大的杂化嵌段共聚物库。DNA订书钉还被设计成携带识别信息，这些信息可以帮助破译哪些聚合物块被钉在一起，即使在复杂的混合物中也是如此。一旦聚合物块被装订在一起，所产生的杂化材料就可以筛选出所需的特性(例如从恶劣环境中保护蛋白质的能力，这对于稳定胰岛素等基于蛋白质的药物是有用的)，然后使用DNA测序策略进行分离和鉴定。这个项目需要跨学科的灵感和技术，这是课堂上经常忽视的科学成就的一个方面。为了解决这种脱节，在现有成功框架的基础上提出了两个教育计划：(1)生物启发-现场和虚拟活动，将生物启发的科学与日常物品联系起来；(2)Sci-athonU-一个合作的学生竞赛，以产生针对全球挑战的跨学科研究建议。这些教育计划的目标是增加获得STEM资源的机会，这些资源强调交流和合作是科学的关键要素。这项拟议的研究计划的长期目标是揭示具有复杂功能的聚合物的设计原则，以推进国家医疗、技术和环境目标，同时提供新的方法来增加学生的动机和留住来自STEM历史上代表性较低的群体的学生。技术综述：可解码聚合物文库有可能彻底改变合成大分子的结构-功能关系的鉴定。虽然蛋白质数据库(PDB)包含了近50,000种不同蛋白质的结构信息，但在合成大分子的多样化结构空间中，表征材料的数量要少得多，这使得结构-功能关系的识别还处于起步阶段。高通量实验对生物化学产生了革命性的影响，RNA序列揭示了蛋白质表达的实时量化和定向进化，产生了独特的蛋白质结构-功能关系。尽管有这些强大的组合方法的影响，但用合成聚合物进行高通量实验仍然很少见。在目前的技术中，每种聚合物都必须并行表征，因为目前还没有快速鉴定从混合物中分离出来的聚合物的策略。在这一根本差距的推动下，这项工作的目的是在整个嵌段共聚物中使用编码聚合物组成的DNA“订书针”，并提供表征聚合物形态和蛋白质稳定性的原理验证的高通量分析。提出了用于设计线状、刷状和星形聚合物形态的合成策略，并提出了识别孤立聚合物的测序方案。这项建议的最终目标是提供一个平台，在一个实验中将聚合物的表征能力从数百种扩展到数千种，从而能够快速识别聚合物结构和高级功能之间的新关系。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。