Genetic Analyses of Heparan Sulfate Function in Cell-Cell Interactions

描述(申请人提供)：细胞迁移是多细胞生命的一个特征，在发育和恶性或病理状态下都是如此。一个分子复杂的胞外环境在指导细胞迁移方面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乙酰肝素蛋白多糖(HSPGs)，它被证明是细胞-细胞信号转导所必需的。在这里，我们建议通过小线虫的典型细胞迁移来研究硫酸乙酰肝素蛋白多糖在细胞迁移中的作用，这些线虫需要热休克蛋白多糖来发挥作用。为此，我们正在使用一种综合的方法，将生化研究与遗传学方法相结合，直接将热休克蛋白G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，我们知道这些细胞迁移已经使用了不同的分子机制，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环境。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主题。我们的研究将使HS结构与细胞和亚细胞定位相关。总括而言，拟议的研究将提供 深入了解迁移细胞用来解释细胞外空间的特定细胞和糖依赖机制。了解迁移细胞的细胞特异性相互作用的基本方面可能最终允许在疾病状态下进行细胞特异性干预。

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.