Sphingolipid Biology And Disease

鞘脂是细胞信号传导途径的重要介质和调节剂。我们的研究主要集中在以鞘糖脂和1-磷酸鞘氨醇为代表的两类鞘脂的作用上。我们的工作旨在定义这些鞘脂的正常功能，并了解它们在疾病过程中的作用。 鞘糖脂（GSL）存在于质膜的外小叶中，并集中在专门的信号结构中。它们以神经节苷脂（含唾液酸的GSL）的形式在神经元细胞中特别丰富。通过对编码GSL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。我们正在使用这些小鼠来发现GSL的功能。 当负责GSL降解的细胞机制有缺陷时，GSL储存疾病导致发生严重的神经变性。例如Tay-Sachs和Gaucher病。我们正试图通过建立疾病的动物模型来了解GSL的积累如何导致神经退行性变。最近的实验已经导致GSL储存疾病中的神经变性模型，其中炎症作为重要组成部分。 鞘氨醇-1-磷酸是一种生物活性鞘脂代谢物，与G蛋白偶联受体家族（称为S1 P受体）结合。SIP受体的刺激触发不同的细胞效应。我们正在破坏S1 P受体和产生鞘氨醇-1-磷酸的酶，以发现该信号系统的生理功能。我们已经发现了这种脂质信号通路在发育过程中血管形成中的独特作用。

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 and sphingosine-1-phosphate. Our work is aimed at defining the normal functions of these sphingolipids and understanding their roles in disease processes. Glycosphingolipids (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 and Gaucher diseases. We are attempting to understand how the accumulation of GSLs cause neurodegeneration through the construction of animal models of the diseases. Recent experiments have led to a model of neurodegeneration in GSL storage diseases with inflammation as an important component. Sphingosine-1-phosphate is a bioactive sphingolipid metabolite that binds to a family of G-protein-coupled receptors, known as S1P receptors. Stimulation of SIP receptors triggers diverse cellular effects. We are disrupting S1P receptors and the enzymes that produce sphingosine-1-phosphate to discover the physiological functions of this signaling system. We have uncovered a unique role for this lipid signaling pathway in the formation of blood vessels during development.