Analysis and Engineering of Cell Function with Nanoscale Cues

描述（由申请人提供）：活组织是嵌入细胞外基质（ECM）的复杂和明确结构中的不同类型细胞的复杂集合体。细胞在组织内的定向和迁移可以通过ECM的组织化和细胞外化学配体的梯度来引导。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至关重要。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，无论是在化学线索的梯度还是细胞基质的纳米级水平控制方面。在此应用中，我们建议开发和测试一系列的仿生微器件相结合的优点，精确定义的纳米地形特征和微尺度的流体流动，导致生成复杂的一套指导线索。我们假设纳米形貌和空间分布的信号配体的组合效应将通过调节粘着斑的定位（和尺寸）和受体结合位点的占用的重新分布而被整合到细胞极性和迁移决定中。我们预计，所提出的工作将导致两个增加了解的细胞极性和指导的建立的基本方面，并允许我们建立更精确和定义的组织工程支架的发展的一般原则。 本研究旨在了解细胞微环境的纳米尺度特征如何控制不同的细胞功能。这些特征模拟天然细胞微环境中发现的细胞外基质，但也可以用于以期望的方式引导细胞行为。因此，本申请中提出的探索性研究将对先进的组织工程问题具有重要意义，与公共卫生具有高度潜在的相关性。

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.