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

深入了解皮肤屏障功能：健康和患病角质层脂质模型的计算机模拟和实验研究

基本信息

批准号：
10466878
负责人：
Paul E Laibinis
金额：
$ 23.29万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10466878
关键词：
3-Dimensional Affect Allergic rhinitis Anabolism Asthma Atopic Dermatitis Binding Biological Cells Ceramides Chemicals Child Cholesterol Complement Computer Models Coupled Data Dehydration Dependence Development Diffusion Disease Disease model Drug Delivery Systems Effectiveness Environment Event Experimental Designs Experimental Models Fibroblasts Functional disorder Future Gel Grain Health Impairment Infection Inflammatory Investigation Knowledge Lateral Length Lesion Lipids Membrane Modeling Molecular Nature Nonesterified Fatty Acids Pathogenesis Pathway interactions Patients Periodicity Permeability Pharmaceutical Preparations Phase Phospholipids Play Publishing Research Rest Rhinitis Role Sampling Severities Severity of illness Skin Stratum corneum Structure Study models Symptoms System Systemic disease Techniques Testing Thinness Toxicant exposure Transdermal substance administration Variant Water Work assault computer framework computer studies crystallinity design effective therapy experimental study improved in silico insight keratinocyte lipid structure models and simulation multi-scale modeling novel organizational structure predictive modeling rational design screening self assembly simulation skin barrier skin disorder therapy development tool treatment strategy

项目摘要

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.

皮肤的功能是防止感染、脱水和化学攻击，对健康和生存至关重要。它的

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Using molecular simulation to understand the skin barrier.

DOI：
10.1016/j.plipres.2022.101184
发表时间：
2022-11
期刊：
PROGRESS IN LIPID RESEARCH
影响因子：
13.6
作者：
Shamaprasad, Parashara;Frame, Chloe O.;Moore, Timothy C.;Yang, Alexander;Iacovella, Christopher R.;Bouwstra, Joke A.;Bunge, Annette L.;McCabe, Clare
通讯作者：
McCabe, Clare

MoSDeF, a Python Framework Enabling Large-Scale Computational Screening of Soft Matter: Application to Chemistry-Property Relationships in Lubricating Monolayer Films

MoSDeF，一种能够对软物质进行大规模计算筛选的 Python 框架：在润滑单层薄膜中的化学性质关系的应用

DOI：
10.1021/acs.jctc.9b01183
发表时间：
2020
期刊：
Journal of Chemical Theory and Computation
影响因子：
5.5
作者：
Summers, Andrew Z.;Gilmer, Justin B.;Iacovella, Christopher R.;Cummings, Peter T.;MCabe, Clare
通讯作者：
MCabe, Clare

Towards molecular simulations that are transparent, reproducible, usable by others, and extensible (TRUE)

DOI：
10.1080/00268976.2020.1742938
发表时间：
2020-03
期刊：
Molecular Physics
影响因子：
1.7
作者：
M. Thompson;Justin B. Gilmer;Ray A. Matsumoto;Co D. Quach;Parashara Shamaprasad;Alexander Yang;C. Iacovella;C. McCabe;P. Cummings
通讯作者：
M. Thompson;Justin B. Gilmer;Ray A. Matsumoto;Co D. Quach;Parashara Shamaprasad;Alexander Yang;C. Iacovella;C. McCabe;P. Cummings

Effect of sphingosine and phytosphingosine ceramide ratio on lipid arrangement and barrier function in skin lipid models.

DOI：
10.1016/j.jlr.2023.100400
发表时间：
2023-08
期刊：
JOURNAL OF LIPID RESEARCH
影响因子：
6.5
作者：
Nadaban, Andreea;Rousel, Jannik;El Yachioui, Dounia;Gooris, Gerrit S.;Beddoes, Charlotte M.;Dalgliesh, Robert M.;Malfois, Marc;Rissmann, Robert;Bouwstra, Joke A.
通讯作者：
Bouwstra, Joke A.

Multiscale Simulation of Ternary Stratum Corneum Lipid Mixtures: Effects of Cholesterol Composition.

DOI：
10.1021/acs.langmuir.2c00471
发表时间：
2022-06-21
期刊：
LANGMUIR
影响因子：
3.9
作者：
Shamaprasad, Parashara;Moore, Timothy C.;Xia, Donna;Iacovella, Christopher R.;Bunge, Annette L.;McCabe, Clare
通讯作者：
McCabe, Clare