Molecular Modeling of Self-Assembling Human Skin Lipids

描述（由申请人提供）：真皮和透皮给药的核心问题是药物通过皮肤最外层角质层（SC）的渗透性低。SC是由死细胞（角质层细胞）嵌入一个富含脂质的环境。水和药物等物质要渗入皮肤，必须通过SC细胞间脂质结构域提供的屏障。实验研究表明，SC的脂质以有序的凝胶或结晶相组织，不像大多数生物膜的典型液晶相，使它们能够作为有效的屏障。脂质组织可归因于SC脂质的独特组成，主要由神经酰胺、游离脂肪酸和胆固醇组成。虽然人们对皮肤脂质的性质了解很多，但角质层中脂质的分子组织的详细情况尚未阐明。实验表明，SC脂质以层状双层结构组织，其中脂质链高度有序，并提出了分子排列模型来支持实验观察。我们建议开发原子细节和粗粒度的分子模型，这些模型将用于未来SC脂类的分子建模研究，以探测脂类分子的组成依赖性和分子排列。基于CHARMM力场的原子模型将专门用于神经酰胺，并将与文献中的游离脂肪酸和胆固醇模型结合使用。在粗粒度模型的开发过程中，将探索不同级别的粗粒度和不同的技术，这些模型将从原子模拟中严格参数化，并通过与实验数据的比较来验证。这项工作将是独特的，因为没有先前的分子模拟研究必不可少的脂质已在文献中报道。提高对SC中脂质组织和相互作用的理解将大大提高我们对皮肤屏障和真皮吸收过程的理解。提出的工作将允许基于分子的洞察脂质组织和结构的组成依赖性，这将澄清异常脂质组成在病变皮肤症状中的作用，有助于开发恢复屏障功能的治疗方法，并为合理设计透皮给药系统提供所需的见解。

DESCRIPTION (provided by applicant): The central problem to dermal and transdermal drug delivery is the low penetration of drugs through the outer most layer of the skin, the stratum corneum (SC). The SC is composed of dead cells (corneocytes) embedded in a lipid-rich environment. For substances such as water and drugs to penetrate into the skin they must pass through the barrier provided by the SC intercellular lipid domains. Experimental studies have shown that the lipids of the SC are organized in ordered gel or crystalline phases, unlike the typical liquid crystalline phases of most biological membranes, enabling them to function as an effective barrier. The lipid organization can be ascribed to the unique composition of the SC lipids, which is composed of mostly ceramides, free fatty acids and cholesterol. While much is known about the nature of the skin lipids, a detailed picture of the molecular organization of lipids in the stratum corneum has not been elucidated. Experimentally it is known that the SC lipids are organized in lamellar bilayer structures in which the lipid chains are highly ordered and models of the molecular arrangement have been proposed to support the experimental observations. We propose to develop both atomistically detailed and coarse-grained molecular models that will be used in future molecular modeling studies of the SC lipids to probe the compositional dependence and molecular arrangement of the lipid molecules. Atomistic models based on the CHARMM forcefield will specifically be developed for the ceramides, and will be used in conjunction with models from the literature for the free fatty acids and cholesterol. Different levels of coarse-graining, and different techniques, will be explored in the development of the coarse-grained models that will be parameterized rigorously from the atomistic simulations and validated through comparison with experimental data. This work will be unique since no prior molecular modeling studies on the lipids essential to the SC have been reported in the literature. An improved understanding of the lipid organization and interactions in the SC would greatly enhance our understanding of the skin barrier and the dermal absorption process. The work proposed will allow molecular- based insight to the compositional dependence of lipid organization and structure, which would clarify the role of abnormal lipid composition in the symptoms of diseased skin, aid development of treatments for restoring barrier function, and provide insights needed for the rational design of transdermal drug delivery systems.