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Molecular and cell biology discoveries in genodermatoses over the past 20 years have allowed scientists and clinicians to understand many important pathways of both normal skin homeostasis and the diseased state. Keratin mutations causing the rare genetic skin blistering disorder epidermolysis bullosa simplex (EBS) is an example of how genetics can help us to understand protein function and patient phenotype. We can now develop cell models of EBS, and tissue culture assays that reproduce stresses causing EBS blistering, as tools to better understand the mechanism by which mutant keratin leads to cell lysis under mechanical stress in the hope for finding pathways to target for therapy. In common diseases, mutations in filaggrin (FLG) have more recently been identified as the major risk factor for atopic dermatitis (AD) and the cause of ichthyosis vulgaris (IV). Until recently, AD was considered an immune disorder, however it is now well understood that the likelihood of developing AD is primarily determined by the effectiveness of the skin barrier. Our initial IV and AD research focused on understanding the FLG mutation landscape in Singapore and we quickly discovered numerous, and population-specific, mutations that were distinct from those observed in European cohorts. We are therefore now developing tissue culture models for AD to provide further insights into the molecular regulation of the cutaneous barrier, with a particular emphasis on the role of filaggrin. As we understand more about the complex genetic interactions and pathways relating to epidermal differentiation and barrier formation, we are starting to find additional regulatory mechanisms that are responsible for homeostasis. One such mechanism of control is the microRNAs. In our institute we have identified a novel post-transcriptional switch that dictates the spatio-temporal and mutually exclusive expression of two alternative gene products from a single transcript. These gene products have opposing actions with a protein that is pro-migratory and a miRNA that promotes homeostasis. When this switch goes awry we observe changes that lead to chronic wounds and cancer invasion. Insights from these tissue culture models of skin disease are helping us to better understanding the normal biology of skin, and we hope lead us to discover new therapies for disease.
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