Tuning multivalency for optimized ligand presentation

调整多价以优化配体呈递

• 批准号: 10470391
• 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/10470391
• 关键词: Address; Attention; Avidity; Biocompatible Materials; Biophysics; Cells; Characteristics; Complement; Complex; Environment; Extracellular Matrix; Goals; Knowledge; Learning; Ligands; Microscopy; Modeling; Molecular; Osteogenesis; Physical Chemistry; Quantitative Structure-Activity Relationship; Regenerative Medicine; Research; Resolution; Reverse engineering; Science; Shapes; Signal Transduction; Specificity; Structure; Surface Plasmon Resonance; Work; cell behavior; combinatorial; design; nano; nanomedicine; nanoscale; programs; receptor; response; simulation

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.

项目总结/摘要 细胞通过在细胞外基质上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。在生物材料科学领域， 在纳米医学中，存在通过呈现来自纳米药物的配体来重建这些复杂动力学的显著需要。 具有最佳呈现的合成基质。然而，制定充分的设计标准是非常具有挑战性的 在这个纳米生物界面，部分原因是相互作用的复杂性以及我们的能力不足， 精确地控制这些大分子特征。我们试图通过开发 定量构效关系（QSAR）模型，使我们能够准确地塑造合成 具有优化的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 显著利用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目标。目标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 了解它们的特性，并学习如何高精度地控制它们的结构。推力2：我们将使用分子 动态（MD）模拟来帮助我们定义这些大分子特征，然后建立QSAR模型来提取 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合力，特异性， 协同性和超选择性。推力4：这些特征对细胞信号传导和配体的影响 将表征定向细胞行为。重点5：我们将把这些新知识应用于各种 应用包括再生医学，纳米医学和作为探针来研究信号转导。这些 制定了五大重点，相互补充，实现我们的长期目标， 生物活性和可定制的配体，用于编程细胞行为。