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

皮肤的表皮屏障在保护身体免受过度水分流失、环境化学物质和微生物感染方面起着至关重要的作用。角质层（SC）屏障由被细胞间脂质双层包围的扁平的富含角蛋白的角质细胞形成。皮肤屏障可能会被损伤、潜在的遗传条件、炎症、环境变化和年龄破坏，导致皮肤干燥、容易受损。对干燥皮肤的研究已经确定了角质细胞积累的增加以及SC脂质组成及其总丰度的改变。我们已经证明，基底膜蛋白层粘连蛋白332随着年龄的增长而丢失，并且老化的皮肤具有降低的SC胆固醇和受损的屏障。我们已经确定，层粘连蛋白332的损失导致角质形成细胞内的胆固醇转运受损，由于破坏丝状肌动蛋白细胞骨架。胆固醇转运的损失反过来导致SC中胆固醇的损失和皮肤屏障的破坏。我们认为层粘连蛋白332的丢失和胆固醇转运的破坏可能是干燥皮肤和其他相关皮肤/头皮病症中皮肤脂质丢失的潜在机制。我们假设层粘连蛋白332的表达在干燥皮肤区域减少。这种减少改变了丝状肌动蛋白通过整联蛋白与基底膜的连接，导致丝状肌动蛋白的损失，这反过来又破坏了胆固醇的转运。丝状肌动蛋白的丢失也可能改变核的形状和大小以及其他细胞功能，如内体成熟。该项目将提供干燥皮肤的机制的证据，并确定治疗干燥皮肤的新策略。

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.