Smart Substrates for Cell Biology and Tissue Engineering

描述（由申请人提供）：本研究计划将开发一个广泛的类活性基质的细胞生物学和组织工程中的应用的机制研究。大多数哺乳动物细胞是粘附性的，并且必须保持附着于蛋白质细胞外基质以存活、增殖、分化和发挥功能。细胞与蛋白质基质的相互作用是由细胞表面受体和基质衍生配体介导的，这些受体和配体不仅用于将细胞定位在组织中，而且还为细胞提供调节线索。在许多情况下，这些线索是动态调制的：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，可以模拟复杂的相互作用模式，是细胞调控的核心。该研究计划将开发一种用于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）配体的活性可以关闭; iii）配体的活性可以在高亲和力状态和低亲和力状态之间可逆地切换。该计划还将开发多功能基板，将这些属性中的两个或更多。该计划将这些活性基质应用于细胞生物学和组织工程中的一组模型问题，以验证这些策略，并实现推进一种对细胞生物学和组织工程技术的实验研究有价值的方法的计划目标。最后，该计划将制定战略，将这些活性基质过渡到生物和生物工程社区的用户。将开发并验证可使用各种配体修饰并结合化学物质以动态控制配体活性的底物类别。该计划将推进一项技术，该技术将对生物学和医学的多个领域产生广泛影响。

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.