Analysis and Engineering of Cell Function with Nanoscale Cues

描述(申请人提供)：活组织是嵌入复杂和明确的细胞外基质(ECM)结构中的不同类型细胞的复杂集合。细胞在组织内的定向和迁移可以由细胞外化学配体的组织和细胞外化学配体的梯度来指导。细胞迁移对于损伤后的组织修复和再生、先天免疫反应、癌症转移和各种发育事件等多种过程是必不可少的。不幸的是，我们分析细胞极化和迁移的能力受到严重限制，因为缺乏能够精确定义细胞微环境的设备，无论是在化学信号的梯度方面，还是在细胞底物的纳米级水平控制方面。在这一应用中，我们建议开发和测试一系列仿生微设备，结合了纳米地形特征的精确定义和微尺度流体流动的优势，从而产生复杂的指导线索集。我们假设，通过调节焦点粘连的定位(和尺寸)和受体结合部位的重新分布，纳米地形和空间分布的信号配体的组合效应将整合到细胞的极性和迁移决定中。我们预计，拟议的工作将增加对建立细胞极性和指导的基本方面的理解，并使我们能够建立开发更精确和更明确的组织工程支架的一般原则。 这项研究旨在了解细胞微环境的纳米尺度特征是如何控制不同的细胞功能的。这些特征模拟了在自然细胞微环境中发现的细胞外基质，但也可以用来以所需的方式指导细胞行为。因此，在这一应用中提出的探索性研究将对高级组织工程问题具有重要意义，具有很高的潜在公共卫生相关性。

DESCRIPTION (provided by applicant): Living tissues are intricate ensembles of cells of different types embedded in complex and well defined structures of extracellular matrix (ECM). Cell orientation and migration within tissues can be guided both by the organization of ECM and gradients of extracellular chemical ligands. Cell migration is essential for such diverse processes as tissue repair and regeneration following injury, innate immune response, cancer metastasis and various developmental events. Unfortunately, our ability to analyze cell polarization and migration is severely limited by the lack of devices capable of precise definition of the cell micro-environment, both in terms of gradients of chemical cues and nano-scale level control of the cell substratum. In this application, we propose to develop and test a series of biomimetic micro-devices combining the advantages of precise definition of both nano-topographic features and micro-scale fluid flows leading to generation of complex sets of guidance cues. We hypothesize that the combined effects of the nano-topography and spatially distributed signaling ligands will be integrated into the cell polarity and migration decisions through regulated localization (and dimensions) of focal adhesions and redistribution of the occupancy of the receptor binding sites. We anticipate that the proposed work will result in both increased understanding of the fundamental aspects of establishment of cell polarity and guidance, and allow us to establish general principles for development of more precise and defined scaffolds for tissues engineering. PUBLIC HEALTH RELEVANCE This research is aimed at understanding of how diverse cell functions are controlled by the nano-scale features of cell micro-environment. These features mimic the extracellular matrix found in the natural cell micro-environment, but can also be used to guide cell behavior in a desired manner. Therefore, the exploratory research proposed in this application will have important implications for advanced tissues engineering problems, of high potential relevance to public health.