Understanding the Regulation of Epidermal Differentiation Genes by Filaggrin in Eczema

特应性湿疹是一种常见的皮肤病，在英国影响多达20%的儿童。失眠对患者及其家人的生活质量有重大影响，包括睡眠障碍、缺课、反复皮肤感染和心理困扰。对于许多儿童来说，湿疹持续到成年，是一种长期，不可治愈的疾病。目前湿疹的治疗是次优的，患者依赖于密集的局部（基于乳膏或软膏的）皮肤治疗，这对患者来说难以坚持并且通常对严重疾病没有效果。对于严重的疾病，有一系列的全身（系统）治疗，但我们还不知道哪些患者会对什么治疗产生反应。虽然湿疹在儿童中的发病率很高，但它是一种研究不足的疾病。有一个很大的未满足的需要，了解疾病的机制。而不是一种疾病，湿疹很可能是不同疾病亚型的组合。了解这些疾病亚型非常重要，这样我们就能识别出哪些患者会对哪些治疗产生反应，因为这最终会导致更成功、更个性化的治疗。皮肤就像一道屏障，阻止细菌、毒素和其他化学物质进入人体。皮肤也是免疫系统的一部分，因为它拥有许多免疫细胞，这些免疫细胞对突破这一屏障的微生物做出反应。越来越明显的是，皮肤屏障的破坏和免疫系统（皮肤对环境和病原体的防御）的变化是湿疹的关键致病因素。湿疹有很强的遗传成分，与皮肤屏障功能的改变有关。FLG基因的突变是湿疹的主要诱发因素，该基因编码聚丝蛋白，聚丝蛋白是皮肤屏障的关键蛋白。我的初步工作表明，当我们的实验室疾病模型中的聚丝蛋白水平降低时，编码构成皮肤屏障的蛋白质（称为表皮分化复合物或EDC）的其他基因的水平也会降低。因此，我们认为通过恢复EDC基因的表达水平，可以改善湿疹的屏障功能。为了观察患有湿疹的儿童/年轻人，其聚丝蛋白水平降低是否也降低了EDC 2的其他基因的表达。了解为什么丝聚蛋白的缺失会导致其他EDC基因的抑制3。为了看看我们是否可以使用小分子和蛋白质来增加EDC蛋白质水平，我将与皇家伦敦医院正在进行的一个项目联系起来，该项目旨在评估1500名患有湿疹的孟加拉国儿童和年轻人。我们将通过胶带剥离获得皮肤样本，并分析EDC蛋白水平。我们将临床评估与我们的EDC分析和聚丝蛋白状态相关联，以帮助识别湿疹内源型（亚型）。然后，我们将通过在实验室中培养皮肤细胞来创建湿疹的生物模型。我们将利用这一点来研究丝聚蛋白水平如何与EDC的其他蛋白质相互作用，以及我们可以改变皮肤细胞以增加EDC蛋白质水平。最后，我们将看看我们是否可以使用增加聚丝蛋白水平的小分子药物或可能直接增加EDC蛋白水平的小分子来增加EDC蛋白水平，以及这是否可以恢复湿疹模型中的皮肤屏障功能。

Atopic eczema is a common skin condition, affecting up to 20% of children in the UK. Eczema has a major impact on the quality of life of patients and their families, including impaired sleep, missed school days, recurrent skin infections and psychological distress. For many children, eczema persists into adulthood and is a long term, incurable condition. Current treatments for eczema are suboptimal with patients relying on intensive topical (cream or ointment based) skin treatments, which are difficult for patients to adhere to and often have no effect on severe disease. For severe disease there are a range of whole body (systemic) treatments but we don't know yet which patients will respond to what treatment. Although eczema has a very high incidence in children, it is an under-researched disease. There is a large unmet need to understand the mechanism of disease. Rather than one disease, eczema is likely to be a combination of different disease subtypes. It is important to understand these disease subtypes to enable us to recognise which patients will respond to which treatments, as this will ultimately lead to more successful and more personalised treatments.The skin acts as a barrier, preventing bacteria, toxins and other chemicals from entering the body. The skin is also part of the immune system, as it hosts many immune cells, which respond to microorganisms that breach this barrier. It is becoming increasingly apparent that both disruption of the skin's barrier and the resulting changes in the immune system (the skin's defences against the environment and pathogens) is a key causative factor in eczema. There is a strong genetic component to eczema associated with altered skin barrier function. Mutations in the FLG gene, which codes for filaggrin, a key protein of the skin barrier, are a major predisposing factor for eczema. My preliminary work has shown that when the filaggrin levels are reduced in our laboratory disease models, the levels of other genes that code for proteins that make up the skin barrier (called the epidermal differentiation complex or EDC) are also reduced. We think that we could improve barrier function in eczema by restoring the level of EDC genes to normal.The main aims to this study are:1. To see if children/young adults with eczema who have reduced levels of filaggrin also have reduced expression of the other genes of the EDC 2. To understand why loss of filaggrin causes suppression of other EDC genes3. To see if we can use small molecules and proteins to increase EDC protein levels I will link into an ongoing project at the Royal London Hospital that aims to assess 1500 Bangladeshi children and young adults with eczema. We will obtain skin samples via tape stripping, and analyse the EDC protein levels. We will correlate the clinical assessment with our EDC analysis and filaggrin status to help identify eczema endotypes (subtypes). We will then create a biological model of eczema by growing skin cells in the laboratory. We will use this to look at how filaggrin levels interact with other proteins of the EDC, and what we could change in skin cells to increase EDC protein levels. Finally, we will see if we can increase EDC protein levels using small molecule drugs that increase filaggrin levels or small molecules that may increase levels of EDC proteins directly, and whether this can restore skin barrier function in our eczema models.