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

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。其 屏障效果几乎完全取决于称为角质层（SC）的薄的外膜， 由死的皮肤细胞嵌入在一个高度有组织的致密的富含脂质的环境。的这种组织 将SC脂质转变成有序的凝胶或结晶相可归因于其独特的组成： 神经酰胺、游离脂肪酸和胆固醇，与大多数生物膜相反，没有磷脂。 有令人信服的证据表明，受损的皮肤屏障，这是巧合的异常， SC脂质的组成、组织和结构是皮肤病发病机制中的主要事件。 疾病甚至一些全身性疾病（例如，哮喘和过敏性鼻炎的发生率 特应性皮炎）。相比之下，SC屏障的有效性是限制局部和 透皮给药更好地理解SC脂质组成， 结构，组织和屏障功能需要：（1）了解皮肤之间的关系 疾病，降低屏障功能和有效的治疗，和（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（预防疾病、毒性 暴露和水分流失）。虽然可以设计和研究模拟SC的实验脂质系统， 对屏障功能与脂质组成和组织之间关系的任何理解， 可以推断;对表征良好的系统进行精确的计算研究将使机械基础 这些关系的一个重要部分。为了补充模拟健康SC的现有模型脂质系统， 我们将实验性地设计和表征新的模型脂质系统， 特应性皮炎（AD）。这些充分表征的合成脂质模型将形成待开发的系统的基础。 通过计算探索。使用多尺度建模方法，无缝结合模拟在 原子和粗粒度（CG）水平，前所未有的洞察分子水平的组织， 在模拟正常和AD-SC的SC脂质平衡组装体中，SC脂质分子之间的相互作用 将获得。还将进行有针对性的实验，以提供验证模型所需的数据 预测（模拟脂质组装体的结构将与光谱，散射和 渗透率研究相应的实验系统）之前的计算框架被使用 用于预测性计算机筛选，以探测与屏障功能相关的各种假设，并确定 SC结构的敏感性，从而屏障功能的脂质组成的变化。相比 在实验研究中，计算模型允许SC模型组成的变化， 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 并且将采用协同实验和计算多尺度方法。

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.