Ultralong Chain Ceramides in Membrane Models of Healthy and Diseased Skin Barrier

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In this project, we propose to investigate the role of ceramide (Cer) molecules with ultralong chains, both in a free-standing mixture with other lipids of the outermost skin layer, the stratum corneum as well as immobilized in the corneocyte lipid envelope. Furthermore, long-periodicity lamellar phases in the skin barrier, which are essential components for life on dry land, will be investigated in molecular detail. In particular, we plan to build and validate stratum corneum models incorporating the corneocyte lipid envelope for the first time. Using these models, we expect to shed light on the putative scaffolding role of the lipids in the corneocyte lipid envelope in healthy skin and establish links on a molecular level between altered corneocyte lipid envelope and increased permeability in skin diseases. In addition, we also expect to expand our understanding of the response of the specific organization of the skin lipid barrier to environmental stressors that are encountered by the skin.Apart from contributing to the basic research of skin (patho)physiology, we expect that the proposed model could significantly aid in designing better therapeutic strategies of skin barrier diseases (such as atopic dermatitis, psoriasis and ichthyoses, which greatly affect the quality of the life of patients). Although topical application of skin-identical lipids or their analogues has a strong potential to repair the skin barrier in such diseases and actually prevent inflammation, deeper understanding of the molecular arrangement of the skin lipid membranes is necessary for a rational design of such therapies.The project is a collaborative effort between a German and a Czech group both working in the field and having demonstrated the synergistic effects of collaboration in several joint publications and through an active exchange of Ph. D. students. The German group specializes in studying biophysical aspects of stratum corneum mixtures with emphasis on investigating the structure and dynamics of lipid molecules in SC model mixtures, the corneocyte lipid envelope, and natural extracts using predominantly 2H and 13C solid-state NMR techniques. The Czech group has great expertise in the chemical synthesis of ceramides including the incorporation of NMR-active isotopes (2H, 13C) and works intensely on model stratum corneum models as well as natural skin and focuses on biophysical techniques (differential scanning calorimetry, x-ray powder diffraction, Fourier transformed infrared spectroscopy) as well as permeability studies on model and natural skin. Thus, a powerful, innovative, and comprehensive combination of researchers with complementary expertise has been assembled to tackle current challenges in the field of skin research.