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

皮肤外层的水渗透屏障（WPB）可防止陆生动物脱水。角质形成细胞间的细胞外脂质膜是WPB的重要组成部分。它们含有具有非常长链（>C30）ω-羟基酰基部分（ω-Cer）的神经酰胺。β-鞘脂的生物合成、细胞内转运、板层体的生物发生及其调控在分子水平上还没有完全了解。然而，这些知识是了解皮肤病理生理学的基础，是靶向治疗的先决条件。我们已经构建了一个神经酰胺合成酶3（CerSS）缺陷小鼠，这是一个致命的WPB故障。CerSS似乎是表皮的基本神经酰胺合酶。该项目的目标是：1）了解CerSS在表皮、板层体和WPB成熟过程中的作用，2）分析CerSS对表皮神经酰胺的生物合成和加工的意义，3）研究CerSS的Hox结构域的潜在调节功能，4）阐明CerSS的细胞内拓扑结构，以及CerS 3所参与的生物合成机制因此，我们希望将CerSS定位在皮肤细胞内并寻找潜在的结合伙伴。预期的体内结果可能有助于更深入地了解人类皮肤病的可能原因，以促进新的治疗方法。

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.