Sphingolipid Biology And Disease

鞘脂生物学与疾病

• 批准号: 6546666
• 负责人: RICHARD L. PROIA
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6546666
• 关键词: G protein; Gaucher's disease; Niemann Pick disease; Sandhoff disease; Tay Sachs disease; angiogenesis; chemical structure function; gangliosidosis; guanosinetriphosphatases; human tissue; inborn lipid storage disorder; laboratory mouse; lipid metabolism; muscle cells; mutant; pathologic process; phosphates; sphingolipidosis; sphingolipids; sphingosine; vascular smooth muscle

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.

鞘脂降解过程中的遗传缺陷会导致一组严重的疾病，称为鞘脂储存疾病。例如泰-萨克斯病、桑德霍夫病、尼曼-皮克病和高谢病。目前，这些疾病中的大多数还没有有效的治疗方法。我们的工作集中在了解疾病的发病机制，以开发新的治疗方法。在这方面，我们已经证明了激活的巨噬细胞在桑德霍夫病的神经元死亡中具有潜在的重要作用。这一发现如果在其他储藏疾病中普遍存在，可能会带来新的治疗方法。我们还在研究鞘磷脂的功能，以了解它们在疾病过程中的作用。为此，我们正在系统地扰乱涉及小鼠鞘脂代谢的基因。最近，我们扰乱了EDG-1的基因，EDG-1是一种G蛋白偶联受体，与鞘氨醇-1-磷酸(SPP)结合。在E12.5和E14.5之间，EDG-1-/-小鼠出现胚胎出血，导致宫内死亡。在突变的胚胎中，血管生成和血管生成均正常。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介导了SPP诱导的迁移反应，这种反应在突变细胞中是有缺陷的，这是由于无法激活小的GTP酶RAC。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的发育过程中是必不可少的。