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。特别是，我们一直在研究鞘脂的功能，以了解它们在疾病过程中的潜在作用。我们正在系统地破坏小鼠鞘脂糖合成基因，以了解这类鞘脂的功能。我们发现，几乎完全消除鞘糖脂合成途径严重损害发育和分化。然而，鞘糖脂结构的部分消除导致了令人惊讶的轻度表型。基于这些结果，我们通过构建小鼠遗传模型，探索了一种新的治疗范式——底物剥夺疗法。异常积累鞘糖脂的Sandhoff病小鼠与部分阻断鞘糖脂合成的小鼠一起繁殖。同时存在GSL合成和降解缺陷的小鼠不再积累糖鞘脂，神经功能改善，寿命延长。这些结果证明了底物剥夺疗法作为鞘脂储存病的潜在治疗范例的有效性。利用鞘脂合成抑制剂n -丁基脱氧诺吉霉素作为治疗鞘脂蓄积性疾病的药物，开发了该方法的实际应用。- Tay-Sachs, Gaucher, Fabry, Sandhoff，鞘脂质病，神经节脂质病

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 particular we have been investigating the functions of sphingolipids to learn their potential roles in the disease process. We are systematically disrupting glycosphingolipid synthesis genes in the mouse to learn the function of this class of sphingolipid. We have found that the near complete elimination of the glycosphingolipid synthesis pathway critically impaired development and differentiation. However, a partial elimination of glycosphingolipid structures resulted in a surprisingly mild phenotype. Based on these results, we have explored a new treatment paradigm -- substrate deprivation therapy -- by constructing a genetic model in mice. Sandhoff disease mice, which abnormally accumulate glycosphinglipids, were bred with mice that were partially blocked in their synthesis of glycosphinglipids. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated glycosphinglipids, had improved neurologic function and had a much longer life span. These results demonstrated the validity of substrate deprivation therapy as a potential treatment paradigm for sphingolipid storage diseases. A practical application of the approach has been developed utilizing N-butlydeoxynojirimycin , a glycosphingolipid synthesis inhibitor, as a drug treatment for the glycosphingolipid storage diseases. - Tay-Sachs, Gaucher, Fabry, Sandhoff, sphingolipidosis, gangliosidosis