A fundamentally important role of the human is skin is to provide a functional barrier between the body’s internal environment and the challenges of the external environment. Healthy, fully developed skin regulates water loss and inhibits the entry of allergens and irritants. Genetic studies have demonstrated the central role of skin barrier in the pathogenesis of eczema (1). When the barrier function is impaired the skin shows dryness and is prone to inflammation, key characteristics of atopic eczema. The processes by which skin cells (keratinocytes) form the human epidermis are complex and dynamic (2) but skin is unique in that the organ can be cultured from primary cells in vitro, making it amenable to experimental approaches not accessible with other tissue systems. The expression of selected candidate genes can be manipulated by siRNA or vector transfection to test their functional effect. Mass spectrometry-based proteomics allows the quantitative, multi-dimensional analysis of cell phenotypes, allowing molecular mechanisms to be characterized in an unbiased approach (3).
This project will investigate the molecular mechanisms responsible for skin barrier formation by combining skin organotypic culture and state-of-the-art proteomic analyses. Specific aims include defining the key regulatory events occurring when cultured keratinocytes differentiate to produce stratified layers and a functional skin barrier and investigating pathways affected by the over-expression or knock-down of genes thought to be involved in the pathogenesis eczema.
Depending on the student’s personal interest, this PhD project will provide the opportunity to work in both clinical and basic laboratories, to gain experience in primary cell culture, skin organotypic models, genetic manipulations, detailed quantitative proteomics and data analysis, through to application of findings in large collaborative datasets (the EAGLE consortium). The project is of direct relevance to understanding the pathomechanisms in atopic skin and this translational research offers the opportunity to define targets for future drug discovery for eczema prevention and treatment.
The supervisory team includes Sara Brown, Professor of Molecular and Genetic Dermatology, a Consultant Dermatologist and Wellcome Trust senior research fellow and Angus Lamond, Professor of Biochemistry in the Centre for Gene Regulation and Expression.
(1) Paternoster et al. Nat Genet. 2015
(2) Simpson CL et al. Nat Rev Mol Cell Biol. 2011
(3) Nat Rev Mol Cell Biol 2015