Sphingolipid Biology And Disease

鞘脂生物学与疾病

• 批准号: 6673831
• 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/6673831
• 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

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.

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。