Sphingolipid Biology and Disease

鞘脂降解的遗传缺陷导致一组严重的疾病，称为鞘脂储存病。例子包括泰-萨克斯病、桑德霍夫病、尼曼-匹克病和戈谢病。目前对这些疾病中的大多数没有有效的治疗方法。我们的工作重点是了解疾病的发病机制，以开发新的治疗方法。在这方面，我们已经证明了活化的巨噬细胞在Sandhoff病神经元死亡中的潜在重要作用。这一发现，如果对其他储存性疾病是普遍的，可能会导致新的治疗方法。我们也在研究鞘脂的功能，以了解它们在疾病过程中的作用。为此，我们正在系统地破坏小鼠鞘脂代谢相关的基因。最近，我们破坏了Edg-1的基因，Edg-1是一种结合鞘氨醇-1-磷酸（SPP）的g蛋白偶联受体。在E12.5和E14.5之间，Edg-1-/-小鼠表现出胚胎出血导致宫内死亡。突变胚的血管发生和血管生成正常。然而，由于血管平滑肌细胞/周细胞的缺乏，血管成熟不完全。我们发现，Edg-1介导spp诱导的迁移反应，由于无法激活小GTPase Rac，该反应在突变细胞中存在缺陷。我们的数据揭示了Edg-1是血管形成所需的第一个g蛋白偶联受体，并表明鞘脂信号在哺乳动物发育过程中是必不可少的。

Inherited defects in the degradation of sphingolipids cause a group of severe disorders known as sphingolipid storage diseases. Examples include Tay-Sachs, Sandhoff, Niemann-Pick and Gaucher diseases. There are currently no effective treatments for the majority of these diseases. Our work has focused on understanding disease pathogenesis in order to develop new therapeutic approaches. In this regard, we have demonstrated a potentially important role for activated macrophages in neuronal death in Sandhoff disease. This finding, if common, to other storage diseases may lead to new approaches to therapy. We are also investigating the functions of sphingolipids to learn their roles in disease processes. To this end we are systematically disrupting genes involved in sphingolipid metabolism in the mouse. Recently, we disrupted the gene for Edg-1, a G-protein coupled receptor that binds sphingosine-1-phosphate (SPP). Edg-1-/- mice exhibited embryonic hemorrhage leading to intrauterine death between E12.5 and E14.5. Vasculogenesis and angiogenesis appeared normal in the mutant embryos. However, vascular maturation was incomplete due to a deficiency of vascular smooth muscle cells/pericytes. We showed that Edg-1 mediates an SPP-induced migration response that is defective in mutant cells due to an inability to activate the small GTPase, Rac. Our data reveal Edg-1, as the first G-protein coupled receptor required for blood vessel formation and show that sphingolipid signaling is essential during mammalian development.