Analysis and Engineering of Cell Function with Nanoscale Cues

描述（由申请人提供）：活组织是不同类型细胞的复杂集合，嵌入复杂且定义良好的细胞外基质（ECM）结构中。细胞在组织内的取向和迁移可以由ECM的组织和细胞外化学配体的梯度来指导。细胞迁移在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中都是必不可少的。不幸的是，由于缺乏能够精确定义细胞微环境的设备，我们分析细胞极化和迁移的能力受到严重限制，无论是在化学线索的梯度方面还是在细胞基质的纳米级水平控制方面。在这个应用中，我们建议开发和测试一系列仿生微型装置，结合纳米地形特征和微尺度流体流动的精确定义优势，从而产生复杂的引导线索。我们假设，纳米形貌和空间分布的信号配体的综合效应将通过调控焦点粘附的定位（和尺寸）和受体结合位点占用的重新分配，整合到细胞极性和迁移决策中。我们预计，这项工作将增加对建立细胞极性和指导的基本方面的理解，并使我们能够建立更精确和明确的组织工程支架发展的一般原则。

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.