Genetic Analyses of Heparan Sulfate Function in Cell-Cell Interactions

描述（由申请人提供）：细胞迁移是多细胞生命的一个特征，无论是在发育阶段还是在恶性或病理状态。分子复杂的细胞外景观在指导细胞迁移中起着至关重要的作用。细胞外空间中最复杂的结构之一是硫酸肝素蛋白多糖（HSPGs），它已被证明是细胞-细胞信号传导所必需的。在此，我们建议利用需要HSPGs的小线虫的细胞迁移来研究硫酸肝素蛋白聚糖在细胞迁移中的功能。为此，我们正在使用一种综合方法，将生化研究与遗传方法相结合，直接将HSPGs的蛋白质和糖结构与其在细胞迁移过程中的功能联系起来。我们的项目将比较不同的细胞迁移，我们知道已经采用不同的分子机制，包括不同的HS糖结构。最后，我们将定义迁移细胞遇到的全球HS景观。为此，我们将使用我们开发的一种新工具，该工具允许在活体动物中直接可视化HS图案。我们的研究将使HS结构与细胞和亚细胞定位相关联。总之，拟议的研究将提供

DESCRIPTION (provided by applicant): Cell migrations are a characteristic of multicellular life, both during development and malignant or, pathological states. A molecularly complex extracellular landscape plays a crucial role in directing migrating cells. One of the most complex structures in the extracellular space is heparan sulfate proteoglycans (HSPGs) that have been shown to be essential for cell-cell signaling. Here we propose to study the function of heparan sulfate proteoglycans in cellular migration using stereotypic cell migrations in the small nematode C. elegans which require HSPGs for function. To this end we are using an integrated approach that combines biochemical studies with genetic approaches to directly correlate protein and sugar structure of HSPGs with their function during cell migration. Our project will compare distinct cell migrations that we know already employ distinct molecular mechanisms, including distinct HS sugar structures. Lastly, we will define the global HS landscape that migrating cells encounter. To this end we will use a novel tool we have developed that allows the direct visualization of HS motifs in living animals. Our studies will allow correlating HS structure with cellular and subcellular localization. In summary, the proposed studies will provide insight into the cell-specific and sugar-dependent mechanisms that migrating cells use to interpret the extracellular space. Understanding fundamental aspects of cell-specific interactions of migrating cells may ultimately allow the cell-specific intervention during diseased states.