Modularity in Oligomeric Phenol Chemistry for Biomodulation of Dental Structures

项目概要/摘要 龋病是一种几乎无处不在的口腔传染病，对人类健康有着巨大的直接和间接影响 关怀、福祉、劳动力和经济。牙科修复干预的质量和寿命 这在很大程度上取决于牙本质的完整性和生物力学特性，牙齿的大块软组织， 由I型胶原蛋白和矿物质组成。广泛使用的树脂基复合材料的形成和可持续性 依赖于对胶原牙本质结构的微机械粘附。我们的跨学科研究团队 为低聚原花青素作为新型生物活性物质来源的实用性提供了广泛的证据 从植物。这些数据支持了一种仿生策略的可行性，这种策略可以提高 基于粘合剂的涂层。从基础临床前研究中获得的见解使人们认识到 模块化低聚植物酚（MOPP）作为化合物的共同结构基序， 结构蛋白如胶原蛋白。由单独的探索性植物化学和生物力学支持 研究以及考虑到结构特征，该项目旨在探索两个生物学 未被充分研究的MOPP类，但化学成分多样，来自维管植物的芪类和间苯三酚 作为潜在的有希望的额外线索。核心假设是中等寡聚芪类化合物 和间苯三酚具有类似但明显不同的结构特征， 适用于牙本质生物调节和生物/生物力学研究的正交工具。总体目标 是扩展牙科工具箱与以前未（der）探索的结构类别的化学多样性， 具有模块化构建模式的生物调节器。 接近牙科-药学界面的总体假设，这两个目的反映了植物分析学 和生物材料角度的互动方法：（目的1）源，纯化，并表征新的模块化 低聚植物酚（MOPPs）;（目的2）建立和比较MOPPs与 人类牙齿的组成部分（牙釉质、牙本质和牙髓细胞）。采用创新的净化和先进的 复杂MOPP的结构表征方法，并执行其并行的最先进的 生物力学评估，该项目具有重要的能力，利用结构的复杂性，并确定 实用和模块化的天然生物调节剂。采用MOPP的自然模块化的潜力， 量身定制的生物调节疗法和提高其临床适用性是该项目的创新方面。 这些研究将为潜在的口腔生物医学奠定坚实的植物化学和生物学基础 芪类化合物和间苯三酚类化合物作为尚未开发的生物活性剂的应用。项目最终成果 是建立新型MOPP作为未来临床前开发的组织生物调节剂。

Project Summary/Abstract Caries is a near-ubiquitous infectious oral disease with an enormous direct and indirect impact on human health care, well-being, workforce, and the economy. The quality and longevity of dental restorative interventions depend largely on the integrity and biomechanical properties of dentin, the tooth’s bulk soft tissue that largely consists of type I collagen and mineral. Formation and sustainability of the widely used resin-based restorations rely on micro-mechanical adhesion to the collagenous dentin structures. Our interdisciplinary research team has produced extensive evidence for the utility of oligomeric proanthocyanidins as novel bioactive materials sources from plants. This body of data supports the feasibility of a biomimetic strategy that enhances the performance of adhesive-based restorations. Insights gained from the underlying pre-clinical studies led to the recognition of modular oligomeric plant phenols (MOPPs) as the common structural motif of compounds that interact with structural proteins such as collagen. Supported by separate exploratory phytochemical and biomechanical studies as well as considering structural characteristics, this project seeks to explore two biologically understudied classes yet chemically diverse of MOPPs, stilbenoids from vascular plants and phloroglucinols from ferns, as potentially promising additional leads. The core hypothesis is that medium-oligomeric stilbenoids and phloroglucinols have analogous yet distinctly different structural characteristics that make these MOPPs suitable for dentin biomodulation and orthogonal tools for biological/biomechanical studies. The overarching goal is to extend the dentistry toolbox with previously un(der)explored structural classes of chemically diverse biomodulators with modular build patterns. Approaching the overall hypothesis at the dentistry-pharmacy interface, the two Aims reflect the phytoanalytical and biomaterial angles of an interactive approach: (Aim 1) Source, purify, and characterize new modular oligomeric plant phenols (MOPPs); (Aim 2) Establish and compare mechanisms of interactions of MOPPs with human teeth constituents (enamel, dentin and pulp cells). Employing innovative purification and advanced structural characterization methodologies for the complex MOPPs and performing their parallel state-of-the-art biomechanical evaluation, the project has significant ability to harness the structural complexity and define the utility and modular natural biomodulation agents. The potential to introduce natural modularity of MOPPs for tailored biomodulatory therapeutics and enhance their clinical applicability are innovative aspects of the project. The studies will build a solid phytochemical and biological foundation for the potential oral biomedical applications of stilbenoids and phloroglucinols as underexplored bioactive agents. The ultimate project outcome is the establishment of new classes of MOPPs as tissue biomodulators for future preclinical development.