Saturday, September 7, 2024
9/7/2024
Abstract/Summary The stratum corneum contains unique species of the sphingolipid ceramide and that unique constellation is essential for formation of the epidermal permeability barrier and is altered in diseases such as atopic dermatitis. These ceramides are composed of fatty acids linked to a set of sphingoid backbones. The species of sphingoid backbones found in the epidermis are highly unique. The premise of this application is that the unique sphingoid backbones found in the epidermis are essential for formation of a fully functioning permeability barrier and that alterations to that composition contributes to compromised barrier function in skin diseases. These concepts have not previously been experimentally addressed. The sphingoid backbones are generated by the serine palmitoyltransferase (SPT) complex, a hetero-oligomeric enzyme composed of four subunits. Three of these four subunits have alternate isoforms. Depending on which isoforms are expressed, SPT generates distinct sphingoid backbones. Our preliminary data demonstrates that during keratinocyte differentiation there is a dramatic increase in the SPT subunits expected to generate the unique sphingoid bases of the epidermis. The ability to genetically alter the expression of the epidermal SPT subunits provides an avenue to directly test the role of epidermal-specific sphingoid backbones in development of the epidermal permeability barrier. We will utilize both organoid culture systems and the intact animal to test this concept. Additionally, we will utilize an animal model of atopic dermatitis to examine the role of these SPT subunits in the etiology of that disease. Through collaboration between experts in keratinocyte biology and skin disorders (Dr. Paller and the Northwestern SBDRC) and lipidomics/the SPT complex (Drs. Wattenberg and Cowart at Virginia Commonwealth), we will fill key gaps in understanding the epidermal lipid barrier through this regulatory mechanism
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