Tuning multivalency for optimized ligand presentation

调整多价以优化配体呈递

• 批准号: 10687216
• 负责人: Adam Joseph Gormley
• 金额: $ 38.4万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687216
• 关键词: Address; Attention; Avidity; Biocompatible Materials; Biophysics; Cell Communication; Cells; Characteristics; Complement; Complex; Environment; Extracellular Matrix; Goals; Knowledge; Learning; Ligands; Modeling; Osteogenesis; Physical Chemistry; Quantitative Structure-Activity Relationship; Regenerative Medicine; Research; Reverse engineering; Science; Shapes; Signal Transduction; Specificity; Structure; Surface Plasmon Resonance; Work; cell behavior; combinatorial; design; molecular dynamics; nano; nanomedicine; nanoscale; programs; receptor; response; superresolution microscopy

Project Summary/Abstract Cells probe their biophysical environment by engaging multiple ligands on the extracellular matrix and in solution resulting in receptor oligomerization and clustering at the nanoscale. In the fields of biomaterials science and nanomedicine, there is a significant need to recreate these complex dynamics by presenting ligands from a synthetic substrate with optimal presentation. However, it is very challenging to develop sufficient design criteria at this nano-bio interface due in part to the complexity of the interactions as well as our insufficient ability to precisely control these macromolecular features. We seek to address this fundamental limitation by developing quantitative structure-activity relationship (QSAR) models that will allow us to accurately shape synthetic multivalent ligands with optimized biophysical dynamics for programmable cell signaling. Our approach significantly leverages a new combinatorial platform developed by the PI to precisely fine tune and study these challenging interactions. To do this, our research program has five major thrusts. Thrust 1: Leveraging our automated platform for multivalent ligand synthesis, we will study the spectrum of available hydrodynamic characteristics and learn how to control their structure with high precision. Thrust 2: We will use molecular dynamic (MD) simulations to help us define these macromolecular features then build QSAR models to extract design criteria. Thrust 3: Using surface plasmon resonance (SPR) and super-resolution microscopy, we will probe ligand-receptor interactions and characterize the macromolecular contributions towards avidity, specificity, cooperativity and super-selectivity. Thrust 4: The implications of these features on cell signaling and ligand directed cell behavior will be characterized. Thrust 5: We will apply this new knowledge to a variety of applications including regenerative medicine, nanomedicine and as probes to study signal transduction. These five major thrusts were developed to complement each other towards our long-term goals for developing highly bioactive and customizable ligands for programed cell behavior.

项目概要/摘要 细胞通过在细胞外基质和溶液中接合多个配体来探测其生物物理环境 导致受体寡聚化和纳米级聚集。在生物材料科学和 纳米医学中，非常需要通过呈现来自纳米粒子的配体来重建这些复杂的动力学。 具有最佳表现力的合成基材。然而，制定足够的设计标准非常具有挑战性 在这个纳米生物界面上，部分原因是相互作用的复杂性以及我们的能力不足 精确控制这些大分子特征。我们寻求通过开发来解决这一根本限制 定量构效关系（QSAR）模型使我们能够准确地形成合成 具有优化生物物理动力学的多价配体，用于可编程细胞信号传导。我们的方法 显着利用 PI 开发的新组合平台来精确微调和研究这些 具有挑战性的互动。为此，我们的研究计划有五个主要重点。主旨 1：利用我们的 多价配体合成的自动化平台，我们将研究可用的流体动力学谱 特性并学习如何高精度控制其结构。主旨 2：我们将使用分子 动态（MD）模拟帮助我们定义这些大分子特征，然后构建 QSAR 模型来提取 设计标准。主旨 3：利用表面等离子共振 (SPR) 和超分辨率显微镜，我们将 探测配体-受体相互作用并表征大分子对亲合力、特异性、 协同性和超选择性。主旨 4：这些特征对细胞信号传导和配体的影响 定向细胞行为将得到表征。主旨 5：我们将把这些新知识应用到各种领域 应用包括再生医学、纳米医学以及作为研究信号转导的探针。这些 制定了五项主要目标，以相互补充，实现我们高度发展的长期目标 用于编程细胞行为的生物活性和可定制配体。