Using Molecular Modeling to Determine Structure and Organization in Skin Lipids

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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.