THE REGULATORY ROLE OF HEPARAN SULFATE PROTEOGLYCANS ON ROBO4

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 李院长领导的研究发现，通过与Slit2和SLIT3相互作用，Robo4在稳定血管网络方面发挥了关键作用。体外研究发现，表达Robo4的人脐静脉内皮细胞与可溶性胞外区的Robo4共同作用，阻断了Slit2的功能，抑制了EC的增殖和迁移，进一步支持了Robo4促进血管生成。这些研究已经确立了Sit-Robo4相互作用在血管生成中的关键促血管生成作用。HSPGs在Robo4功能和信号转导中的调控作用，结合细胞表面配体结合和内皮细胞功能分析，可以极大地提高我们对HSPGs在Robo4功能和信号转导中的调控作用的认识和理解。资源重组蛋白的表达和高亲和力配体的体外筛选与合成相结合，将为合理设计调控Robo4血管生成功能的糖胺多糖类药物提供平台。

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.