Sphingolipid Biology And Disease

鞘脂降解的遗传缺陷导致一组称为鞘脂储存病的严重疾病。例子包括Tay-Sachs、Sandhoff、Niemann-Pick和Gaucher病。目前，对大多数这些疾病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，我们已经证明了一个潜在的重要作用，激活的巨噬细胞在神经元死亡的桑德霍夫病。这一发现，如果共同的，其他储存疾病可能会导致新的治疗方法。我们还在研究鞘脂的功能，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参与小鼠鞘脂代谢的基因。最近，我们破坏了Edg-1的基因，Edg-1是一种结合1-磷酸鞘氨醇（SPP）的G蛋白偶联受体。Edg-1-/-小鼠在E12.5和E14.5之间表现出胚胎出血，导致宫内死亡。在突变胚胎中血管发生和血管生成正常。然而，由于缺乏血管平滑肌细胞/周细胞，血管成熟不完全。我们发现，Edg-1介导的SPP诱导的迁移反应是有缺陷的突变细胞，由于无法激活小的GT3，Rac。我们的数据揭示了Edg-1作为血管形成所需的第一个G蛋白偶联受体，并表明鞘脂信号传导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.