Smart Substrates for Cell Biology and Tissue Engineering

描述（由申请人提供）：本研究项目将为细胞生物学的机制研究和组织工程的应用开发一类广泛的活性底物。大多数哺乳动物细胞是粘附的，必须保持附着在蛋白质细胞外基质上，才能存活、增殖、分化和发挥功能。细胞与蛋白质基质的相互作用是由一系列细胞表面受体和基质衍生的配体介导的，它们不仅可以定位细胞在组织中的位置，还可以为细胞提供调节线索。在许多情况下，线索是动态调制的：也就是说，从基质中呈现的配体的组成随时间而变化。细胞和基质之间的动态相互作用的实验研究是困难的，仍然需要新的工具来模拟复杂的相互作用模式，这是细胞调节的核心。该研究计划将开发一种创建动态底物的策略，其中固定化配体的活性可以在电气控制下实时切换。该计划将开发模型底物，其中：i)配体的活性可以打开；Ii)配体的活性可以被切断；Iii)配体的活性可以在高亲和态和低亲和态之间可逆切换。该计划还将开发包含两种或多种这些特性的多功能基板。该计划将这些活性底物应用于细胞生物学和组织工程中的一系列模型问题，以验证这些策略，并满足推进一种对细胞生物学和工程组织技术的实验研究有价值的方法的计划目标。最后，该计划将制定将这些活性底物转化为生物和生物工程社区用户的策略。可以用各种配体修饰的底物类别，并纳入对配体活性进行动态控制的化学物质，将被开发和验证使用。该项目将推进一项技术，该技术将在生物学和医学的几个领域产生广泛的影响。

DESCRIPTION (provided by applicant): This research program will develop a broad class of active substrates for mechanistic studies in cell biology and applications in tissue engineering. Most mammalian cells are adherent and must remain attached to the protein extracellular matrix in order to survive, proliferate, differentiate and function. The interactions of cells with the protein matrix are mediated by a host of cell-surface receptors and matrix-derived ligands, which serve not only to localize cells in tissue but also to provide cells with regulatory cues. In many instances, the cues are dynamically modulated: that is, the composition of ligands presented from the matrix changes over time. Experimental studies of dynamic interactions between cell and matrix are difficult and still in need of new tools that can mimic the complex patterns of interactions that are central to cellular regulation. This research program will develop a strategy for creating dynamic substrates wherein the activities of immobilized ligands can be switched in real-time under an electrical control. The program will develop model substrates wherein: i) the activities of ligands can be switched on; ii) the activities of ligands can be switched off; iii) the activities of ligands can be reversibly switched between high and low affinity states. The program will also develop multifunctional substrates that incorporate two or more of these properties. The program will apply these active substrates to a set of model problems in cell biology and tissue engineering in order to validate these strategies and meet the program goals of advancing an approach that will be valuable to experimental studies in cell biology and technologies for engineering tissue. Finally, the program will develop strategies for transitioning these active substrates to users in the biological and bioengineering communities. Classes of substrates that can be modified with a variety of ligands and that incorporate the chemistries for dynamic control over ligand activity will be developed and validated for use. This program will advance a technology that will have broad impact across several areas in biology and medicine.