THE ROLE OF ECM MECHANICS IN REGULATING CAPILLARY MORPHOGENESIS

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 ECM 力学对二维细胞反应（例如粘附、扩散、运动、增殖甚至分化）的重要性已得到广泛认可和充分表征。然而，内在机械线索对 3D 培养中细胞的长期表型反应的影响仍不清楚，这些表型变化背后的分子机制也是如此。将细胞表型的变化与 3D 基质力学联系起来的努力部分由于缺乏合适的材料系统而受到阻碍。理想情况下，合适的材料系统应提供独立于粘附配体密度和蛋白水解敏感性可预测地调节基材机械性能的方法。除了材料限制之外，由于缺乏合适的方法来评估局部细胞-材料界面的机械性能，剖析 ECM 力学对 3-D 细胞功能的影响的努力也受到了阻碍。 大多数研究人员选择利用材料弹性和粘弹性特性的批量测量，并将这些特性与细胞功能相关联。不幸的是，这些并不能充分描述当地的微环境。我们建议利用基于聚乙二醇和纤维蛋白原的独特生物合成混合水凝胶。 此外，我们建议开发新的方法来测量这种材料的局部机械性能。以下三个具体目标构成了拟议的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The importance of ECM mechanics on 2-D cell responses (e.g., adhesion, spreading, motility, proliferation, and even differentiation) is widely recognized and well characterized. However, the effects of intrinsic mechanical cues on longer-term phenotypic responses of cells in 3-D culture remain undefined, as do the molecular mechanisms underlying these phenotypic changes. Efforts to relate changes in cell phenotype with substrate mechanics in 3-D have been hindered in part by the lack of suitable material systems. Ideally, a suitable material system should provide the means to predictably tune substrate mechanical properties independently from adhesion ligand density and proteolytic sensitivity. In addition to material limitations, efforts to dissect the influence of ECM mechanics on cell function in 3-D have been hampered by the lack of suitable methods to assess mechanical properties at the local cell-material interface. Most researchers have instead chosen to utilize bulk measurements of a material's elastic and viscoelastic properties and to correlate these with cell function; unfortunately, these do not adequately depict the local microenvironment. We proposed to utilize a unique biosynthetic hybrid hydrogel based on poly(ethylene glycol) and fibrinogen. Furthermore, we proposed to develop novel methodologies to measure the local mechanical properties this material. The following three specific aims constitute the proposed study.