Tuning multivalency for optimized ligand presentation

调整多价以优化配体呈递

• 批准号: 10911591
• 负责人: Adam Joseph Gormley
• 金额: $ 7.01万
• 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/10911591
• 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.

项目摘要/摘要 细胞通过在细胞外基质和溶液中与多种配体接合来探测其生物物理环境 导致纳米级的受体寡聚和聚类。在生物材料科学领域 纳米医学，通过呈现来自A的配体来重新创建这些复杂动力学 具有最佳呈现的合成基材。但是，制定足够的设计标准非常具有挑战性 在这种纳米生物界面上，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。我们试图通过发展来解决这一基本限制 定量结构活性关系（QSAR）模型，该模型将使我们能够准确塑造合成 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并研究这些平台 具有挑战性的互动。为此，我们的研究计划有五个主要的推力。推力1：利用我们的 多价配体合成的自动化平台，我们将研究可用流体动力学的光谱 特征并学习如何以高精度控制其结构。推力2：我们将使用分子 动态（MD）模拟，以帮助我们定义这些大分子特征，然后构建QSAR模型以提取 设计标准。推力3：使用表面等离子体共振（SPR）和超分辨率显微镜，我们将 探针配体 - 受体相互作用，并表征大分子对亲和特异性的贡献 合作性和超级选择性。推力4：这些特征对细胞信号和配体的影响 定向细胞行为将被表征。推力5：我们将把这些新知识应用于各种 包括再生医学，纳米医学和作为研究信号转导的探针的应用。这些 开发了五个主要的推力，以相互补充，以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自定义的配体。