Tuning multivalency for optimized ligand presentation

项目摘要/摘要 细胞通过在细胞外基质和溶液中结合多个配体来探测其生物物理环境 导致受体在纳米尺度上的齐聚和聚集。在生物材料科学和技术领域 纳米医学，有很大的需要重建这些复杂的动力学，通过呈现来自 具有最佳外观的合成基材。然而，制定足够的设计标准是非常具有挑战性的。 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没有足够的能力 精确控制这些大分子特征。为了解决这一根本限制，我们开发了 定量结构-活性关系(QSAR)模型，将使我们能够准确地塑造 具有用于可编程细胞信号传递的优化生物物理动力学的多价配体。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。为了做到这一点，我们的研究计划有五个主要推动力。推力1：利用我们的 自动化的多价配体合成平台，我们将研究可用的流体力学光谱 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，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 探测配体-受体的相互作用，并表征大分子对亲和力，特异性， 协作性和超选择性。推力4：这些特征对细胞信号和配体的影响 我们将描述定向细胞的行为。推力5：我们将把这一新知识应用于各种 应用包括再生医学、纳米医学和作为研究信号转导的探针。这些 我们制定了五大重点，相辅相成，朝着我们高度发展的长期目标迈进。 生物活性和可定制的配体，用于编程细胞行为。

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.