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

健康和患病皮肤屏障膜模型中的超长链神经酰胺

• 批准号: 412106983
• 负责人: Professor Dr. Daniel Huster, Ph.D.
• 金额: --
• 依托单位: Institut für Medizinische Physik und Biophysik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/412106983?language=en
• 关键词: Ultralong; Chain; Ceramides; Membrane; Models

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.

在这个项目中，我们建议研究具有超长链的神经酰胺（Cer）分子的作用，无论是在与最外层皮肤层、角质层的其他脂质的独立混合物中，还是固定在角质细胞脂质包膜中。此外，长周期性层状相在皮肤屏障，这是生活在干燥的土地上的基本组成部分，将在分子的细节进行研究。特别是，我们计划建立和验证角质层模型纳入角质细胞脂质包膜的第一次。使用这些模型，我们期望阐明健康皮肤中角质细胞脂质包膜中脂质的假定支架作用，并在皮肤疾病中改变角质细胞脂质包膜和增加渗透性之间的分子水平上建立联系。此外，我们还希望扩大我们对皮肤脂质屏障的特定组织对皮肤所遇到的环境应激因素的反应的理解，除了有助于皮肤（病理）生理学的基础研究之外，我们期望所提出的模型可以显著地帮助设计更好的皮肤屏障疾病的治疗策略（如特应性皮炎、牛皮癣和鱼鳞病，这些疾病极大地影响了患者的生活质量）。虽然局部应用皮肤相同的脂质或其类似物具有修复此类疾病中的皮肤屏障并实际预防炎症的强大潜力，更深入地了解皮肤脂质膜的分子排列对于合理设计此类疗法是必要的。该项目是德国和捷克小组之间的合作努力，这两个小组都在该领域工作，并证明了合作在几个联合出版物，并通过积极交流博士学位。学生该德国小组专门研究角质层混合物的生物物理方面，重点研究SC模型混合物中脂质分子的结构和动力学，角质细胞脂质包膜和天然提取物，主要使用2H和13C固态NMR技术。捷克团队在神经酰胺的化学合成方面拥有丰富的专业知识，包括NMR活性同位素（2H，13C）的掺入，并在模型角质层模型以及天然皮肤上进行了大量工作，并专注于生物物理技术（差示扫描量热法，X射线粉末衍射，傅立叶变换红外光谱）以及模型和天然皮肤的渗透性研究。因此，一个强大的，创新的，全面的研究人员与互补的专业知识组合已经组装，以解决目前在皮肤研究领域的挑战。