THE ROLE OF ECM MECHANICS IN REGULATING CAPILLARY MORPHOGENESIS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 ECM机制对2-D细胞应答的重要性（例如，粘附、扩散、运动、增殖和甚至分化）被广泛认可并被很好地表征。然而，在3-D培养细胞的长期表型反应的内在机械线索的影响仍然不确定，因为这些表型变化的分子机制。在3-D中将细胞表型的变化与基质力学联系起来的努力部分地受到缺乏合适的材料系统的阻碍。理想地，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底机械性质的手段。除了材料的限制，努力解剖ECM力学对细胞功能的影响，在3-D已受到阻碍，缺乏合适的方法来评估机械性能在当地的细胞-材料界面。 大多数研究人员选择利用材料的弹性和粘弹性的批量测量，并将这些与细胞功能相关联;不幸的是，这些并不能充分描述局部微环境。我们提出利用一种独特的生物合成的混合水凝胶的基础上聚（乙二醇）和纤维蛋白原。 此外，我们建议开发新的方法来测量这种材料的局部力学性能。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.