Nanostructured Matrices for Cancer Cell Biology

项目总结(见说明)： 癌症生物学的一个广泛挑战是开发具有生理学意义的细胞培养模型。 与此相关的是，寄居细胞表现出疾病下的复杂行为。此外，为细胞提供统一一致的微环境的细胞培养模型将减少通常观察到的细胞行为的分布，因此将导致可用于定量比较不同细胞群体行为的可靠分析。拟议的工作旨在改进在塑料培养皿上进行的平面培养的使用，这种培养通常不足以捕捉相关的细胞行为，以及对癌症生物学一直很重要的常见Matrigel三维基质的使用，尽管这种自然基质的属性可变且组成不完全。拟议的项目将采用分子方法来开发两类定义的矩阵。一种是基于纳米颗粒的底物，具有重要意义，因为这种图案可以用来限制焦点粘连的大小，使它们与组织内细胞中观察到的内容以及什么时候更相关 排列成轨迹模式为细胞提供了一条可重复的迁移路径，消除了异质行为的一大来源。第二种方法基于由多肽和多肽两亲分子自组装的三维矩阵，对于使用完全定义的组合物具有重要意义，该组合物还允许在结合多肽和蛋白质基序时具有广泛的灵活性。这两种设计都强调在纳米尺度上对材料性质的控制，无论是在图案化的细胞外基质的尺寸上，还是在三维基质中的纤维尺寸上，因此都模仿了蛋白质基质的物理特征。该项目强调基质的开发和表征，但也包括具有脑和胰腺癌生物学和医学专业知识的研究人员，为评价基质提供了一个真正的试验台。该项目的广泛目标是开发无与伦比的培养系统，为细胞提供支持复杂生物学功能的微环境，并使细胞功能的可靠、定量分析成为可能。因此，这项工作如果成功，将在基础研究实验室以及在高通量筛查中使用基于细胞的分析的项目中发挥重要作用，并可能作为治疗癌症过程中组织再生的材料。 癌症。

PROJECT SUMMARY (See instructions): A broad challenge in cancer biology is the development of cell culture models that are physiologically relevant in that the resident cells display the complex behaviors that underiie disease. Further, cell culture models that provide a uniform and consistent microenvironment to the cells will decrease the distribution of cellular behaviors that are typically observed and therefore will lead to robust assays that can be used to quantitatively compare the behaviors of different cell populations. The proposed work is intended to improve on the use of planar cultures performed on plastic dishes that are often insufficient to capture relevant cell behaviors, and the common Matrigel three-dimensional matrix that has been important to cancer biology, notwithstanding the variable properties of and incompletely defined composition of this natural matrix. The proposed project will pursue molecular approaches to developing two classes of defined matrices. One is based on nanopatterned substrates and is significant because the patterns can be used to constrain the sizes of focal adhesionsmaking them more relevant to what is observed in cells within tissueand when arranged into track patterns provides a reproducible path for cells to migrate along, removing a large source of heterogeneous behavior. The second approach is based on three-dimensional matrices that are selfassembled from peptides and peptide amphiphiles and is significant for the use of a completely defined composition that also permits wide flexibility in incorporating peptide and protein motifs. Both designs emphasize the control of material properties at the nanoscaleeither in the dimensions of patterned extracellular matrix or the sizes of the fibrils in the three dimensional matricesand therefore mimic the physical features of protein matrix. The project emphasizes the development and characterization of the matrices, but also includes investigators with expertise in the biology and medicine of brain and pancreafic cancer, providing a real test-bed for evaluating the matrices. The broad goal of the project is to develop culture systems that are unmatched for providing cells with a microenvironment that supports complex biological functions and that enable robust, quantitative assays of cell function. This work, if successful, will therefore be important in basic research laboratories but also in programs to use cell-based assays in high throughput screens and possibly as materials that provide for regeneration of tissue in the treatment of cancer.