Insights into skin barrier function: In silico and experimental studies of healthy and diseased stratum corneum lipid models

皮肤作为抵抗感染、脱水和化学攻击的屏障对健康和生存至关重要。它的 屏障的有效性几乎完全依赖于称为角质层(SC)的薄外膜，角质层 由死亡的皮肤细胞嵌入高度组织、致密、富含脂肪的环境中组成。这一组织 SC脂形成有序的凝胶或晶相可归因于其独特的组成：主要 神经酰胺、游离脂肪酸和胆固醇，与大多数生物膜不同，不含磷脂。 有令人信服的证据表明，受损的皮肤屏障与 SC脂的组成、组织和结构是皮肤发病的首要事件 疾病，甚至一些全身性疾病(例如，哮喘和过敏性鼻炎的发生在 特应性皮炎)。相比之下，SC屏障的有效性是一个中心问题，限制了专题和 经皮给药。提高了对SC脂质成分之间的关系的理解， 结构、组织和屏障功能需要：(1)了解皮肤之间的关系 疾病，降低的屏障功能和有效的治疗，以及(2)开发新的技术 降低屏障功能(更有效地输送药物)或改善屏障功能(防止疾病、有毒物质 暴露和水分损失)。虽然可以设计和研究模拟SC的实验脂质系统， 任何对屏障功能与脂质成分和组织之间关系的理解只能 可以推断；对特征良好的系统进行准确的计算研究将允许机械基础 这些关系需要清楚地加以探讨。为了补充现有的模拟健康SC的模型脂质系统， 我们将试验性地设计和表征新的模型脂质系统，它模仿患病的皮肤，特别是 特应性皮炎(AD)。这些具有良好特性的合成脂质模型将构成系统的基础 通过计算进行了探索。使用多尺度建模方法，在 原子级和粗粒度(CG)级别，对分子级别组织的前所未有的洞察，以及 模拟正常和AD-SC的SC脂平衡集合体中SC脂分子间的相互作用 将会被获得。还将进行有针对性的实验，以提供验证该模型所需的数据 预测(模拟脂质组件的结构将与光谱、散射和 在使用计算框架之前对相应的实验系统进行渗透性研究) 用于计算机筛查中的预测，以探讨与屏障功能相关的各种假说，并确定 SC结构和屏障功能对脂类成分变化的敏感性。与之形成鲜明对比的是 实验研究，计算模型允许SC模型的组成变化为 很容易调整。这项工作是独一无二的，因为自组装结构将构成建模研究的基础 并将采用实验和计算相结合的多尺度方法。

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 membrane, called the stratum corneum (SC), which consists of dead skin cells embedded in a highly organized dense lipid-rich environment. This organization of the SC lipids into ordered gel or crystalline phases can be ascribed to its unique composition: mostly ceramides, free fatty acids and cholesterol, with no phospholipids in contrast to most biological membranes. There is compelling 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., the occurrence of asthma and allergic rhinitis in patients with atopic dermatitis). In contrast, the effectiveness of the SC barrier is a central problem limiting topical and transdermal drug delivery. An improved understanding of the relationship between SC lipid composition, structure, and organization and barrier function 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). While experimental lipid systems that mimic the SC can be designed and studied, any understanding of the relationship between barrier function and lipid composition and organization can only be inferred; accurate computational studies on well-characterized systems would allow the mechanistic basis of these relationships to be clearly probed. To complement existing model lipid systems that mimic healthy SC, we will experimentally design and characterize new model lipid systems that mimics diseased skin, specifically atopic dermatitis (AD). These well-characterized synthetic lipid models will form the basis of the systems to be explored computationally. Using a multi-scale modeling approach that seamlessly combines simulations at the atomistic and coarse-grained (CG) levels, unprecedented insight into the molecular level organization of, and interactions between, SC lipid molecules in equilibrated assemblies of SC lipids modeling normal and AD-SC will be obtained. Targeted experiments will also be performed to provide the data needed to validate the model predictions (structures of the simulated lipid assemblies will be compared with spectroscopic, scattering and permeability studies on the corresponding experimental systems) before the computational framework is used for predictive in silico screening to probe various hypothesis related to barrier function and determine the sensitivity of the SC structure and thus barrier function to changes in lipid composition. In contrast to experimental studies, the computational models allow for variations in the composition of the SC models to be easily adjusted. The work is unique since self-assembled structures will form the basis of the modeling studies and a synergistic experimental and computational multiscale approach will be employed.