Defining the Biological Functions of Novel Lipids in Healthy and Wounded Skin

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Healthy skin forms a barrier that is essential for preventing infection and loss of water from our bodies. Loss of this barrier occurs during common skin diseases such as psoriasis and eczema, and allows infection during chronic wounds. Lipids (fats) are required to maintain the barrier, but little is known regarding how they do this, with the role of skin lipids in disease a major under-researched area. In Cardiff and Vanderbilt, we discovered several families of lipids that are generated by skin or by blood cells that migrate to the skin during response to injury, or in skin disease. Our preliminary data suggests that several of these may be important in maintaining the health of skin and preventing disease. They are made by a family of proteins (enzymes) called lipoxygenases (LOXs) and include two types of lipids, called phospholipids and ceramides. In this study we will use a number of approaches to determine the roles of the lipids in regulating skin biology. The studies may lead to development of new treatments for common skin disorders and chronic wounds, conditions that cause significant morbidity in a large section of our population. The primary objective of this study is to determine how lipids discovered by the Cardiff and Vanderbilt groups regulate skin biology. To do this we will use reconstituted human skin, mouse models and patient samples.Aims: (1) Determine the structure and localization of the lipids in human skin. In this aim we will determine the structures of all the lipids still to be fully characterized. We will also use imaging and other methods to determine where the lipids are located in skin (which layers of the epidermis). Both healthy skin and samples from patients with inflammatory skin disorders will be studied. (2) Determine how the lipids regulate skin health and disease at the molecular level. We propose that the lipids may help regulate skin through two different molecular processes. These include regulation of an important protein called PPAR and through regulating how blood cells that have migrated into the skin behave during health and disease. We will study these events using a 3D cultured human skin system, and in a murine model of wounding in vivo. (3) Characterise regulation of skin gene expression by LOX-derived lipids. To identify pathways by which the lipids regulate skin health, the enzymes that generate them will be removed in cultured human skin using an approach called siRNA. A global screening approaches called RNAseq will then determine changes in gene expression in specific skin compartments and how these are mediated. (4) Discover new lipids formed in skin disease. The total number and types of lipids are present in skin is unknown. As part of a European Research Council grant, we are developing new methods for studying lipids that will be applied to our studies of skin lipids in this project. Lipids will be catalogued in samples of healthy skin, and in biopsies from patients with the common skin disorders, psoriasis and eczema, with a view to identifying new lipids that regulate skin health and disease. These studies will determine how lipids regulate skin biology, and may lead to design of new therapies for inflammatory skin diseases and wounds.