THE REGULATORY ROLE OF HEPARAN SULFATE PROTEOGLYCANS ON ROBO4

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。子项目的主要支持 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。 列出的子项目总成本可能 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。 Dean Li博士的领导工作发现，Robo 4通过与Slit 2和Slit 3相互作用，在稳定血管网络方面发挥着关键作用。体外研究观察到，用Robo 4的可溶性胞外结构域处理表达Robo 4的人脐静脉EC阻断了Slit 2功能并抑制了EC增殖和迁移，进一步支持Robo 4促进血管生成。 这些研究已经确立了Slit-Robo 4相互作用在血管生成中的关键促血管生成作用。结构特征的HS和CS的生产和突变内皮细胞系的开发，结合细胞表面配体结合和内皮细胞功能测定，可以大大提高我们的知识和理解的HSPGs在Robo 4功能和信号转导的调节作用。Resource重组蛋白表达与高亲和力配体的体外筛选和合成相结合，将为合理设计调节Robo 4血管生成功能的糖胺聚糖药物提供平台。

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 leading work of Dr. Dean Li found that Robo4 plays a key role in stabilizing vascular networks by interacting with both Slit2 and Slit3. In vitro studies observed that treating Robo4-expressing human umbilical vein ECs with a soluble extracellular domain of Robo4 blocked Slit2 function and inhibited EC proliferation and migration, further supporting that Robo4 promotes angiogenesis. These studies have established the critical proangiogenic role of Slit-Robo4 interaction in angiogenesis. The production of structurally characterized HS and CS and the development of mutant endothelial cell lines, combined with cell-surface ligand binding and endothelial cell function assays, can greatly advance our knowledge and understanding of the regulatory role of HSPGs in Robo4 function and signaling. The combination of Resource recombinant protein expression, and the in vitro screening and synthesis of high affinity ligands will provide a platform for the rational design of glycosaminoglycan agents for modulation of Robo4 function in angiogenesis.