Sphingolipid Biology and Disease

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。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。我们正在系统地干扰小鼠的神经鞘糖脂合成基因，以了解这类鞘糖脂的功能。我们发现，糖鞘糖脂合成途径的几乎完全消除严重损害了发育和分化。然而，糖鞘糖脂结构的部分消除导致了令人惊讶的温和的表型。基于这些结果，我们探索了一种新的治疗模式-底物剥夺疗法-通过构建小鼠的遗传模型。桑德霍夫病小鼠不正常地积累糖鞘脂，与糖鞘脂合成部分受阻的小鼠进行饲养。GSL合成和降解同时存在缺陷的小鼠不再积累糖磷脂，神经功能得到改善，寿命大大延长。这些结果证明了底物剥夺疗法作为一种潜在的鞘磷脂储存疾病治疗范式的有效性。利用N-丁基脱氧神经节苷脂合成抑制剂N-丁基脱氧神经节苷脂作为治疗鞘糖脂贮积性疾病的药物，开发了该方法的实际应用。--Tay-Sachs、Gaucher、Fabry、Sandhoff、鞘脂沉积症、神经节苷脂沉积症

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