Regulation of Sphingolipid Homeostasis and Implications for Disease
This project addresses mechanisms for regulating sphingolipid homeostasis. Sphingolipids play a structural role in membranes, controlling fluidity and forming sphingolipid metabolites also have key functions in signal transduction. Recent discovery of the conserved ORMDL protein family represents a major advance in understanding regulation of sphingolipid synthesis. Initial work on regulation of sphingolipid synthesis via transcriptional control and phosphorylation of the Orm proteins has been done in yeast in the Chang lab. The importance of understanding Orm function in mammalian cells is underscored by numerous diseases involving sphingolipid synthesis and degradation. Recent therapeutic strategies in metabolic diseases such as obesity and diabetes have focused on the regulation of sphingolipid synthesis. In this proposed collaborative effort we will combine the expertise on mammalian sphingolipids of the Shayman lab and the expertise in diabetes of the Arvan lab to dissect the molecular mechanism of the mammalian ORMDL proteins.