SC COBRE: HUMAN ALKALINE CERAMIDASE REGULATION OF ANGIOGENESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 血管生成，即从原有的血管形成新的毛细血管的过程，对于适当的器官发育和组织修复是必不可少的。然而，无法控制的血管生成可能会导致诸如慢性炎症、糖尿病视网膜病变、类风湿性关节炎和实体瘤生长等病理变化。血管生成受细胞因子、趋化因子、生长因子和抑制物的协同调节。除了这些蛋白质因子外，一些脂质因子已被证明在介导血管生成中发挥重要作用。其中最突出的是鞘氨醇-1-P(S1P)及其类似物，它通过与EDG受体家族的G蛋白偶联受体结合来增强生长因子诱导的血管生成。S1P是鞘磷脂的代谢物。它是由鞘氨醇通过鞘氨醇的作用产生的。神经鞘氨醇是神经酰胺通过神经酰胺酶的作用而产生的。最近，一些研究表明神经酰胺诱导内皮细胞生长停滞和凋亡。这些结果表明，鞘脂代谢的调节可能控制着血管的生成。我们的结果首次证明了人碱性植物神经酰胺酶是调节神经酰胺和S1P类似物二氢神经鞘氨醇-1-P水平的关键酶。这使人类碱性植物神经酰胺酶成为肿瘤血管生成和生长的化疗干预的潜在靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Angiogenesis, the process of formation of new capillaries from preexisting blood vessels, is essential for the proper organ development and tissue repair. However, uncontrollable angiogenesis may lead to pathologies such as chronic inflammation, diabetic retinopathy, rheumatoid arthritis, and growth of solid tumors. Angiogenesis is coordinately regulated by cytokines, chemokines, growth factors, and inhibitors. In addition to these proteinaceous factors, several lipid factors have been shown to play an important role in mediating angiogenesis. Prominent among them are sphingosine-1-P (S1P) and its analogs which potentiates growth factor-induced angiogenesis by bonding to G protein coupled receptors of the Edg receptor family. S1P is a metabolite of sphingolipids. It is generated from sphingosine through the action of sphingosine kianse. Sphingosine in turn is generated from hydrolysis of ceramide through the action of ceramidases. More recently, several studies demonstrate that ceramide induces growth arrest and apoptosis of endothelial cells. These results suggest that regulation of metabolism of sphingolipids may control angiogenesis. Our results for the first time demonstrate that the human alkaline phytoceramidase is a key enzyme that regulates the levels of ceramides and the analog of S1P, dihdyrosphingosine-1-P. This establishes the human alkaline phytoceramidase as a potential target for chemotherapeutic interventions of tumor angiogenesis and growth.