SC COBRE: REGULATION OF MAMMALIAN FATTY ACID ALPHA-HYDROXYLASE GENE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In higher vertebrates, nerve conduction is greatly facilitated by myelin, a lipid-rich membrane that wraps around the axon. Myelin is formed by oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). A number of devastating demyelinating diseases threaten human health, and few effective treatments exist. To develop better treatment for these diseases, we must understand the mechanisms involved in myelination. The overall goal of this study is to elucidate roles myelin lipids in myelination and cell signaling, with particular emphasis on 2-hydroxy galactolipids and cell migration. Myelin has distinct lipid and protein constituents. Galactosylceramide (GalCer) and sulfatide make up approximately 30% of total myelin lipids, and more than half of these galactolipids contain 2-OH fatty acids as their N-acyl chains. No other mammalian tissues contain such high concentrations of 2-OH fatty acids. The significance of the high 2-OH galactolipid content in myelin is not fully understood, but the current state of knowledge offers exciting possibilities. While the striking abundance of 2-OH galactolipids in myelin has been well-recognized, our knowledge about the synthesis of 2-OH galactolipids is limited. To fill this gap, we have cloned and characterized the human fatty acid 2-hydroxylase gene, FA2H, that is highly expressed in brain. We have developed sensitive gas chromatography/mass spectrometry-based assays for fatty acid 2-hydroxylase activity and tissue 2-OH fatty acids. Subsequently, we have provided strong evidence that FA2H is responsible for the synthesis of myelin 2-OH galactolipids in both CNS and PNS. In these studies, we demonstrated that 2-hydroxylation of galactolipids dramatically increased during myelination. More recently, we found that FA2H knockdown significantly enhanced migration of Schwannoma cells. There findings led us to further develop the project to investigate roles of FA2H and 2-OH sphingolipids in cell signaling. In addition to the myelin project, we have developed a successful collaboration to determine the roles of FA2H and 2-OH sphingolipids in epidermis, which is another tissue with high levels of 2-OH sphingolipids. We obtained strong evidence that FA2H and 2-OH sphingolipids play critical roles in formation of permeability barrier function of epidermis.