CAREER: Sequence Defined Peptoid Materials for Selective Biodegradation

人体内的细胞产生许多类型的分子来降解环境中的物质。这些分子可以是小而非特异性的，如高活性自由基，也可以是大而更有针对性的，如酶。通过简单的台式分析来感知存在哪些降解分子的能力，将使癌症或炎症等疾病状态的表征更加有效。因此，该项目将研究类肽的降解行为，类肽是一类合成分子，具有选择性降解一种生物分子（自由基）而不能降解另一种生物分子（酶）的潜力。这种选择性将使基于肽的传感器的设计能够无创地识别生物环境中存在的降解分子，并且这种知识也将影响用于生物医学植入物的具有明确降解特性的新材料的设计。该计划还将包括在高中、本科生和研究生层面的教育和推广活动，以扩大不同群体对生物材料研究的参与。具体来说，它将制定一个指导计划，以促进来自STEM领域代表性不足群体的学生在一年一度的德克萨斯生物材料日上的互动。活性氧/氮（ROS/RNS）和基质金属蛋白酶（MMPs）是细胞外基质重塑的关键驱动因素，特别是在疾病和炎症期间。可降解肽和蛋白质通常被用作ROS和MMP传感器；然而，一个关键的挑战是交叉反应性和对一种降解物种的有限选择性。非天然肽（或n-取代甘氨酸）提供了一个有吸引力的平台，由于其蛋白水解稳定的n-取代聚酰胺骨架和对ROS/RNS的潜在选择性易感性，可以解决这些限制。此外，肽类保留了生物分子的单体序列定义，但利用了扩展的侧链功能，这可能对混合底物中的MMP降解具有更高的特异性。拟议的研究活动将结合合成与质谱和新的降解分析：1)定义非天然肽类对生物相关氧化降解机制的选择性和敏感性，2)确定MMPs对混合底物降解特异性的单个序列影响，以及3)评估基于肽类的生物材料作为同时检测ROS和MMPs混合物的平台。这些研究将对复杂生物环境中肽类降解行为产生根本性的见解，并使肽类传感器和材料的开发应用于组织工程、疾病建模和诊断筛选。此外，拟议的教育活动将建立一个新的指导计划，以加强来自德克萨斯州少数民族服务机构和传统黑人学院和大学的学生在年度德克萨斯州生物材料日的参与。该指导计划的最佳实践将通过网络研讨会进行分享，以促进在全国其他九个生物材料日上广泛实施类似计划。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 SummaryThe cells in the human body produce many types of molecules that degrade materials in their environment. These molecules can be small and non-specific, such as highly reactive radicals, or they can be large and more targeted, such as enzymes. The ability to sense which degradative molecules are present through simple bench top assays would enable more efficient characterization of disease states such as cancer or inflammation. This project will therefore study the degradation behavior of peptoids, a class of synthetic molecules that offers the potential to degrade selectively one type of biomolecule (radical species) but not another (enzymes). This selectivity will enable the design of peptoid-based sensors to non-invasively identify which degradative molecules are present in a biological environment, and this knowledge will also impact the design of new materials with well-defined degradation properties for use in biomedical implants. The proposed project will also include educational and outreach activities at the high school, undergraduate, and graduate student level to broaden the participation of diverse groups in biomaterials research. Specifically, it will develop a mentoring program to facilitate interactions among students from underrepresented populations in STEM at the annual Texas Biomaterials Day. Technical Summary Reactive oxygen/nitrogen species (ROS/RNS) and matrix metalloproteases (MMPs) are critical drivers of extracellular matrix remodeling, especially during disease and inflammation. Degradable peptides and proteins are commonly exploited as ROS and MMP sensors; however, a key challenge is cross-reactivity and limited selectivity toward one type of degradative species. Non-natural peptoids (or N-substituted glycines) offer an attractive platform with which to address these limitations due to their proteolytically-stable N-substituted polyamide backbone and potential selective susceptibility to ROS/RNS. In addition, peptoids preserve the monomer sequence definition of biomolecules but utilize an expanded class of side chain functionalities, which may access higher specificity to MMP degradation in hybrid substrates. The proposed research activities will combine synthesis with mass spectrometry and new degradation assays to: 1) define the selectivity and sensitivity of non-natural peptoids toward biologically relevant oxidative mechanisms of degradation, 2) determine monomer sequence effects on the specificity of hybrid substrate degradation by MMPs, and 3) assess peptoid-based biomaterials as platforms to simultaneously detect mixtures of ROS and MMPs. These studies will lead to fundamental insights regarding peptoid degradation behavior in complex biological environments and enable the development of peptoid-based sensors and materials for applications in tissue engineering, disease modeling, and diagnostic screening. In addition, the proposed educational activities will establish a new mentoring program to enhance the participation of students from Minority Serving Institutions and Historically Black Colleges and Universities in Texas at the annual Texas Biomaterials Day. Best practices from this mentoring program will be shared via webinar to facilitate the broad implementation of similar programs at the nine other Biomaterials Days across the country.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.