Around half of people with eczema do not carry the known genetic mutation that weakens their skin barrier, and researchers want to find out why. This matters because eczema affects millions of people, yet current treatments often fail to address the underlying causes. The known mutation—in the filaggrin gene—explains only some cases. This project targets the other half: people whose eczema stems from different genetic glitches, including variations in the number of copies of related genes, which have been overlooked because their repetitive DNA sequences are hard to study. The researcher will use skin organoids grown in the lab to test candidate genes identified from genome-wide studies and from her own analysis of gene activity. She will also sequence the epidermal differentiation complex—a cluster of genes crucial for skin barrier function—in both children and adults with eczema, comparing them to healthy controls. Significant findings will be checked against DNA from ongoing clinical trials. If successful, this work will clarify which molecular pathways drive skin barrier breakdown in different patient groups. That could eventually help stratify patients for targeted therapies, moving eczema care beyond trial-and-error prescribing. For now, the research is fundamental science: it bridges the gap between genetic discovery and clinical application, but does not promise an immediate treatment.
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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 <50% of eczema patients carry a FLG null mutation and mechanisms in FLG wild-type cases are not well understood. FLG intragenic copy number variation has a dose-dependent effect on eczema, but structural variation in related genes with repetitive sequence has not been studied in depth. These genes may offer a target for therapeu tic intervention. Genome-wide association studies have identified >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.
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