The role of the Laminin 332-Actin-Cholesterol axis in skin conditions with altered lipid profiles.

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The skin's epidermal barrier plays a vital role in protecting the body from excessive water loss, environmental chemicals and microbial infection. The stratum corneum (SC) barrier is formed of flattened keratin rich corneocytes surrounded by intercellular lipid bilayers. The skin barrier can be disrupted by injury, underlying genetic conditions, inflammation, environmental changes and by age leading to dry, easily-damaged skin. Investigations of dry skin have identified increased corneocytes accumulation as well as alterations in both the composition of SC lipids and their total abundance. We have demonstrated that the basement membrane protein laminin 332 is lost with age and that aged skin has reduced SC cholesterol and an impaired barrier. We have identified that loss of laminin 332 leads to impaired cholesterol transport within keratinocytes due to a disruption of the filamentous actin cytoskeleton. The loss of cholesterol transport in turn leads to a loss of cholesterol in the SC and disruption of the skin barrier. We believe that the loss of laminin 332 and disruption of cholesterol transport may be the mechanism underlying loss of skin lipids in dry skin and other related skin/scalp conditions. We hypothesise that the expression of laminin 332 is reduced in areas of dry skin. This reduction alters the attachment of filamentous actin via integrins to the basement membrane leading to the loss of filamentous actin which in turn disrupts cholesterol transport. The loss of filamentous actin may also alter nuclear shape and size and other cellular functions such as endosome maturation. This project will provide evidence of the mechanism underlying dry skin and identify new strategies for the treatment of dry skin.