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Using Molecular Modeling to Determine Structure and Organization in Skin Lipids

使用分子模型确定皮肤脂质的结构和组织

基本信息

批准号：
8254493
负责人：
Clare McCabe
金额：
$ 19.54万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254493
关键词：
Allergic rhinitis Asthma Behavior Biological Cells Ceramides Cereals Chemicals Cholesterol Cholesterol Esters Data Dependence Dermal Disease Drug Delivery Systems Effectiveness Environment Event Gel Goals Health Human Infection Investigation Knowledge Lateral Lead Lipids Literature Measurement Membrane Microscopy Modeling Molecular Molecular Models Molecular Probes Nature Nonesterified Fatty Acids Palmitic Acids Pathogenesis Patients Pharmaceutical Preparations Phase Phospholipids Physiology Play Positioning Attribute Process Property Protocols documentation Reporting Research Rest Role Skin Staging Stratum corneum Structure Symptoms System Systemic disease Techniques Testing Time Topical agent Toxicant exposure Transdermal substance administration Water Work absorption assault base body water loss chemical dehydration cholesteryl sulfate design effective therapy heuristics improved insight lipid structure molecular dynamics molecular modeling nanoscale novel prevent public health relevance research study self assembly simulation skin disorder therapy development treatment strategy

项目摘要

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.

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薄的外层，称为角质层（SC），它由嵌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相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，与大多数生物膜相比，不存在磷脂。越来越多的证据表明，与SC脂质组成、组织和结构异常同时发生的皮肤屏障受损，是皮肤病甚至一些全身性疾病（例如，特应性皮炎患者发生哮喘和变应性鼻炎）发病的主要原因。相反，SC屏障的有效性是真皮和透皮给药的核心问题。我们需要更好地了解脂质组成与脂质组织之间的关系，并最终了解SC脂质中化学物质的运输：(1)了解皮肤病、屏障功能降低和有效治疗之间的关系；(2)开发降低屏障功能（更有效地输送药物）或改善屏障功能（防止疾病、毒性暴露和水分流失）的新技术。SC脂质组成和组织的实验研究是关键但缓慢的，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脂质的原子细节和粗粒度模型进行分子建模研究，以探索脂质分子的分子排列及其自组装成薄片。这项工作将是独特的，因为没有先前的分子模拟研究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）将被执行来分析形成的纳米级结构和驱动自组装过程的相互作用。首先，将进行简单的二元和三元脂质混合物的模拟，以探索每种脂类在SC中的作用。这些研究的结果将从逻辑上导致模拟含有不同游离脂肪酸的现实水合混合物的SC模型系统。实验中已知的神经酰胺和胆固醇可以自组装成与SC非常相似的结构。该结构对脂质混合物的组成和神经酰胺、游离脂肪酸和胆固醇的比例的敏感性也将被探索。还将研究局部药物（包括水）在SC脂质中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(dr。Neubert， Bouwstra和Wertz)和其他人。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Examining the phase transition behavior of amphiphilic lipids in solution using statistical temperature molecular dynamics and replica-exchange Wang-Landau methods.

DOI：
10.1063/1.4816520
发表时间：
2013-08
期刊：
The Journal of chemical physics
影响因子：
0
作者：
Lili Gai;T. Vogel;Katie A. Maerzke;C. Iacovella;D. Landau;P. Cummings;C. McCabe
通讯作者：
Lili Gai;T. Vogel;Katie A. Maerzke;C. Iacovella;D. Landau;P. Cummings;C. McCabe

Development of a coarse-grained water forcefield via multistate iterative Boltzmann inversion.

通过多态迭代玻尔兹曼反演开发粗粒度水力场。