Using Molecular Modeling to Determine Structure and Organization in Skin Lipids

描述（由申请人提供）：皮肤作为感染、脱水和化学攻击的屏障的功能对健康和生存至关重要。它的屏障效果几乎完全取决于薄的外层，称为角质层（SC），它由嵌入在高度组织化的富含脂质的环境中的死皮细胞组成。SC脂质组织成有序的凝胶或结晶相可归因于其独特的组成; SC主要由神经酰胺、游离脂肪酸和胆固醇组成，并且与大多数生物膜相反，不存在磷脂。越来越多的证据表明，与SC脂质的组成、组织和结构异常相一致的受损的皮肤屏障是皮肤病甚至一些全身性疾病（例如，特应性皮炎患者中哮喘和过敏性鼻炎的发生）。相比之下，SC屏障的有效性是皮肤和透皮药物递送的中心问题。需要更好地理解脂质组成与脂质组织以及最终与SC脂质内化学物质运输的关系：（1）了解皮肤病、屏障功能降低和有效治疗之间的关系，以及（2）开发新技术，（更有效地提供药物）或改善它（以防止疾病，有毒物质暴露和水分流失）。SC脂质组成和组织的实验研究是关键的，但缓慢，只能推断脂质组成和皮肤屏障功能之间的联系。因此，我们建议使用SC脂质的原子详细和粗粒度模型来进行分子建模研究，以探测脂质分子的分子排列及其自组装成laminate。这项工作将是独特的，因为没有以前的分子建模研究的脂质系统必不可少的SC已在文献中报道。模拟（分子动力学和蒙特卡罗）将被用来分析形成的纳米级结构和驱动自组装过程的相互作用。最初，将进行简单的二元和三元脂质混合物的模拟，以探测SC中每种脂质类的作用。这些研究的结果将在逻辑上导致模拟包含不同游离脂肪酸的真实水合混合物的模型SC系统，神经酰胺和胆固醇，从实验到自我，组装成与SC非常相似的结构。还将探讨结构对脂质混合物组成和神经酰胺、游离脂肪酸和胆固醇的比例的敏感性。还将研究SC脂质中局部药物（包括水）的转运及其对脂质组织的影响。在拟议研究的所有阶段，我们将把我们的结果与我们的合作者（Neubert，Bouwstra和Wertz博士）和其他人报告的合成脂质混合物的实验数据进行比较。 公共卫生相关性：对角质层（皮肤的最外层）中脂质组织的更好理解将大大增强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合物在患病皮肤症状中的作用，帮助开发恢复屏障功能的治疗方法，并提供经皮给药系统的合理设计所需的见解。

DESCRIPTION (provided by applicant): The Skin's function as a barrier to infection, dehydration and chemical assault is critical to health and survival. Its barrier effectiveness rests almost entirely in the thin, outer layer, called the stratum corneum (SC), which consists of dead skin cells embedded in a highly organized lipid-rich environment. This organization of the SC lipids into ordered gel or crystalline phases can be ascribed to its unique composition; the SC is composed of mostly ceramides, free fatty acids and cholesterol, and, in contrast with most biological membranes, no phospholipids are present. There is mounting evidence that an impaired skin barrier, which is coincidental with abnormalities in composition, organization and structure of the SC lipids, is the primary event in the pathogenesis of skin disease and even some systemic diseases (e.g., occurrence of asthma and allergic rhinitis in patients with atopic dermatits). In contrast, it is the effectiveness of the SC barrier that is the central problem for dermal and transdermal drug delivery. An improved understanding of the relationship of lipid composition to lipid organization and ultimately to transport of chemicals within the SC lipids is needed: (1) to understand the relationship between skin disease, reduced barrier function and effective treatment, and (2) to develop new techniques for either reducing barrier function (to deliver drugs more effectively) or improving it (to protect against disease, toxic exposure and water loss). Experimental investigations of SC lipid composition and organization are critical but slow, and can only infer the linkage between lipid composition and skin barrier function. Therefore, we propose to perform molecular modeling studies using both atomistically detailed and coarse-grained models of the SC lipids to probe the molecular arrangement of the lipid molecules and their self-assembly into lamellae. This work will be unique since no prior molecular modeling studies on lipid systems essential to the SC have been reported in the literature. Simulations (molecular dynamics and Monte Carlo) will be performed to analyze the nano-scale structures that are formed and the interactions that drive the self-assembly process. Initially, simulations of simple binary and ternary lipid mixtures will be conducted to probe the role of each lipid class in the SC. The results from these studies will lead logically to simulations of a model SC system containing a realistic hydrated mixture of different free fatty acids, ceramides and cholesterol that are known from experiments to self-assembles into a structure that closely resembles the SC. The sensitivity of the structures to the lipid mixture composition and ratio of ceramides, free fatty acids and cholesterol will also be probed. Transport of topical agents, including water, in the SC lipids and their effect on lipid organization will also be studied. At all stages in the proposed research we will compare our results with experimental data for synthetic lipid mixtures reported by our collaborators (Drs. Neubert, Bouwstra and Wertz) and others. PUBLIC HEALTH RELEVANCE: An improved understanding of lipid organization in the stratum corneum, the outermost layer of the skin, 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.