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特征，在发育和恶性或病理状态期间都是如此。分子复杂的细胞外景观在引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乙酰肝素蛋白聚糖（HSPG），其已被证明是细胞-细胞信号传导所必需的。在这里，我们提出了研究硫酸乙酰肝素蛋白多糖在细胞迁移中的功能，在小型线虫C。需要HSPG来发挥功能的线虫。为此，我们正在使用一种综合的方法，将生物化学研究与遗传方法相结合，直接将HSPGs的蛋白质和糖结构与它们在细胞迁移过程中的功能相关联。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，我们将使用一种新的工具，我们已经开发，允许直接可视化的HS图案在活的动物。我们的研究将允许关联HS结构与细胞和亚细胞定位。总之，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细胞特异性和糖依赖性机制。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期间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.