Molecular mechanisms in atopic skin. (360G-Wellcome-106865_Z_15_Z)

Atopic skin is characterized by widespread barrier dysfunction. Null mutations in the gene encoding filaggrin (FLG) represent a strong risk factor for atopic eczema, but 20 other eczema risk loci but their functional relevance is unclear. My recent transcriptome analysis indicates the importance of pathways within the extracellular space, lipid metabolism and stress response leading to skin barrier dysfunction. I propose to address outstanding questions to translate the significant investment in genetic research for clinical application. My key goals are to develop established skin organotypic c ulture models for testing eczema candidate genes and to investigate the role of structural variation within the epidermal differentiation complex. Selected candidate genes will be tested in vitro, offering a platform to separate the multiple genetic and environmental factors in this complex trait. I will use next-generation sequencing combined with conventional methodologies to test whether structural variation in additional epidermal differentiation genes affect eczema risk in both paediatric a nd adult case collections. Significant findings will be assessed using DNA collected as part of collaborators' ongoing clinical trials. These studies will improve understanding of eczema pathogenesis and start to bridge the gap between molecular genetics and clinical care.