In vivo model systems to develop filaggrin as a drug target in atopic disease

我们最近发现了导致湿疹的主要基因，以及与湿疹相关的一系列其他疾病，如过敏和湿疹相关性哮喘。微丝蛋白基因使一种对皮肤屏障形成至关重要的蛋白质在大约10%的人群中因基因突变而完全失活，导致皮肤渗漏。允许细菌、过敏原和化学物质等异物进入人体的皮肤。免疫系统会看到这些异物，这会导致皮肤发炎(湿疹)，并作为次要事件，导致其他系统，如肺部(哮喘)。微丝蛋白基因是两种不同类型药物的理想靶点，这两种药物既可以挽救某些有缺陷的基因并重新启动它们，也可以增强基因的活性。我们已经证明，这些药物确实可以挽救或促进细胞和皮肤中微丝蛋白的产生。这笔赠款旨在开发接近模拟人类微丝蛋白缺陷的动物模型。这将使我们能够剖析疾病的机制，更重要的是，测试针对这种基因的新治疗系统。该项目有可能治疗英国400多万人，或全球1000多万人。如果及早使用，这些药物可以预防湿疹和相关疾病的发生，如过敏、某些类型的哮喘和花粉热。

We recently discovered the major gene that causes eczema and a host of other conditions associated with eczema, such as allergies and eczema-associated asthma. The filaggrin gene, which makes a protein essential for skin barrier formation, is completely deactivated by genetic mutations in about 10% of the population, leading to ?leaky? skin that allows foreign material such as bacteria, allergens and chemicals to enter the body. These foreign substances are seen by the immune system and this leads to inflammation of the skin (eczema) and as a secondary event, other systems such as the lungs (asthma). The filaggrin gene is an ideal target for two different types of drugs that can eithr rescue certain defective genes and switch them back on again, or boost the activity of a gene. We have shown that these drugs can indeed rescue or boost filaggrin production in cells and skin. This grant is designed to develop animal models that closely mimic the human filaggrin defects. This will allow us to dissect out the disease mechanisms and importantly, to test the new therapy systems aimed at this gene. This project has the potential to treat over 4 million people in the UK, or 10s of millions worldwide. If administered early, such drugs could prevent the onset of eczema and associated diseases, such as allergies and certain types of asthma and hay fever.