Functions of the ceramide synthase 3 and very long chain sphingolipids during establishment of the epidermis and its water permeability barrier

• Applicant: Privatdozent Dr. Roger Sandhoff
• Subject Area: Biochemistry
• Term: from 2010 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 170949669

The water permeability barrier (WPB) in the outer layer of the skin prevents land dwelling animals from desiccation. Extracellular lipid lamellae between the corneocytes are an essential part of the WPB. They contain ceramides with very long chain (>C30) omega-hydroxy acyl moieties (h-Cer). The biosynthesis of h-sphingolipids, their intracellular transport, the biogenesis of lamellar bodies, and their regulations are incompletely understood at a molecular level. However, this knowledge is fundamental for the understanding of skin pathophysiology, a prerequisite for targeted therapy. We have constructed a ceramide synthase 3 (CerSS) deficient mouse, which is showing a lethal WPB breakdown. CerSS appears to be the fundamental ceramide synthase of the epidermis. The aims of this project are: 1) to understand the role of CerSS during maturation of the epidermis, of lamellar bodies, and of the WPB, 2) to analyse the significance of CerSS for the biosynthesis and processing of epidermal ceramides, 3) to Investigate a potential regulatory function of the Hox domain of CerSS, 4) to elucidate the intracellular topology of CerSS, and the biosynthetic machinery of which CerS3 is part of. Thus, we want to localize CerSS intracellularly in the skin and search for potential binding partners. The expected in vivo results may help to gain deeper insight into the possible causes of human skin diseases in order to facilitate new ways of therapy.

• DFG Programme: Research Grants