Sphingolipid Biology And Disease

鞘脂是细胞信号通路的重要介质和调节剂。我们的研究主要集中在鞘脂糖（GSLs）和鞘脂-1-磷酸两类鞘脂的作用上。我们的工作旨在确定这些鞘脂的正常功能，并了解它们在疾病过程中的作用。GSLs存在于质膜的外小叶中，集中在特殊的信号结构中。它们在神经元细胞中以神经节苷脂（含GSLs的唾液酸）的形式尤其丰富。通过对编码GSLs合成酶的基因进行遗传破坏，我们创造了一系列表达有限鞘糖脂结构的小鼠。我们正在用这些老鼠来发现GSLs的功能。当负责GSL降解的细胞机制有缺陷时，GSL储存疾病导致深度神经变性发生。例如泰-萨克斯病、桑德霍夫病和戈谢病。我们正试图通过构建动物模型来了解GSLs的积累是如何导致神经退行性变的。

Sphingolipids are important mediators and regulators of cell signaling pathways. Our studies have focused on the actions of two classes of sphingolipids represented by glycosphingolipids (GSLs) and sphingosine-1-phosphate. Our work is aimed at defining the normal functions of these sphingolipids and understanding their roles in disease processes. GSLs are found in the outer leaflet of the plasma membrane and are concentrated in specialized signaling structures. They are particularly abundant in neuronal cells in the form of gangliosides (sialic acid containing GSLs). Through genetic disruption of genes that encode synthetic enzymes for GSLs, we have created a series of mice that express limited glycosphingolipid structures. We are using these mice to discover the functions of GSLs. When the cellular machinery responsible for GSL degradation is defective, GSL storage diseases result in which profound neurodegeneration occurs. Examples are Tay-Sachs, Sandhoff and Gaucher diseases. We are attempting to understand how the accumulation of GSLs cause neurodegeneration through the construction of animal models of the diseases. Our major accomplishments this year include a demonstration the expanded macrophage/microglial population in the brain of Sandhoff disease mice is compounded by the infiltration of cells from the periphery. Coincident with the cellular infiltration was an increased expression of macrophage-inflammatory protein 1alpha (MIP-1alpha), a leukocyte chemokine, in astrocytes. Deletion of MIP-1alpha expression resulted in a substantial decrease in infiltration and macrophage/microglial-associated pathology together with neuronal apoptosis in Sandhoff disease mice. These mice without MIP-1alpha showed improved neurologic status and a longer lifespan. The results indicate that the pathogenesis of Sandhoff disease involves an increase in MIP-1alpha that induces monocytes to infiltrate the brain, expand the activated macrophage/microglial population, and trigger apoptosis of neurons, resulting in a rapid neurodegenerative course We also continued our studies on the G-protein coupled receptor for sphingosine-1-phosphate, S1P1. To determine the precise role of the S1P1 receptor on T-cells, we established a T-cell-specific S1P1 knock-out mouse. The mutant mice showed a block in the egress of mature T-cells into the periphery. The expression of the S1P1 receptor was up-regulated in mature thymocytes, and its deletion altered the chemotactic responses of thymocytes to sphingosine 1-phosphate. The results indicated that the expression of the S1P1 receptor on T-cells controls their exit from the thymus and entry into the blood and, thus, has a central role in regulating the numbers of peripheral T-cells..