Molecular Modeling of Self-Assembling Human Skin Lipids

描述(申请人提供)：皮肤和经皮给药的中心问题是药物对皮肤最外层角质层(SC)的低渗透率。SC由死细胞(角膜细胞)组成，嵌入在富含脂肪的环境中。水和药物等物质要渗入皮肤，就必须通过SC细胞间脂类结构域提供的屏障。实验研究表明，与大多数生物膜的典型液晶相不同，SC的脂类以有序的凝胶或晶相组织，使它们能够起到有效的屏障作用。脂肪组织的形成与SC脂的独特组成有关，SC脂主要由神经酰胺、游离脂肪酸和胆固醇组成。虽然关于皮肤脂质的性质已知很多，但角质层中脂质分子组织的详细情况尚未阐明。在实验上，已知SC脂是以层状双层结构组织的，其中的脂链高度有序，并提出了分子排列模型来支持实验观察。我们建议开发原子精细和粗粒度的分子模型，用于未来SC脂类的分子模拟研究，以探索脂分子的组成依赖和分子排列。基于CHARMM力场的原子论模型将专门为神经酰胺开发，并将与文献中关于游离脂肪酸和胆固醇的模型结合使用。在开发粗粒度模型时，将探索不同的粗粒度级别和不同的技术，这些粗粒度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进行验证。这项工作将是独一无二的，因为以前没有关于SC所必需的脂质的分子模拟研究在文献中报道过。更好地了解SC中的脂质组织和相互作用将极大地增强我们对皮肤屏障和皮肤吸收过程的了解。这项工作将使基于分子的洞察脂质组织和结构的成分依赖性，这将澄清异常的脂质组成在疾病皮肤症状中的作用，帮助开发恢复屏障功能的治疗方法，并为合理设计经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.