Cytokine regulation of skin barrier function

描述(申请人提供)：特应性皮炎(AD)患者的皮肤炎症包括树突状细胞、肥大细胞和T细胞。从患者样本和小鼠模型中都有证据表明AD中几个辅助性T细胞亚群的功能。疾病中有明显的遗传因素；过敏家族史是AD的最强预测因素之一，而表皮分化复合体(EDC)的组成部分微丝蛋白(flaggrin，Flg)基因的突变已成为AD发生的易感因素。IL-4和IL-13促进特应性反应，减少一些EDC基因的表达，这些基因对屏障功能至关重要。仍然没有答案的主要问题之一是，导致AD的缺陷是在皮肤还是在特应性免疫系统，或者疾病是否需要这两个系统的缺陷。回答这个问题的核心是了解免疫系统和皮肤，特别是角质形成细胞，如何在分子水平上相互作用。该项目的总体目标是确定促进特应性炎症发展的细胞因子对角质形成细胞基因表达和功能的相互作用，长期目标是找到治疗疾病的靶向途径。我们的假设是，促过敏细胞因子改变了角质形成细胞的生物学，改变了屏障功能，促进了过敏原暴露的增加。这一假说将从两个方面进行检验，一是在小鼠模型系统中检验微丝蛋白突变与Th2免疫增强之间的相互作用，二是确定STAT6在调节角质形成细胞基因表达方面的功能。总之，这些研究将提供对过敏性炎症过程中产生的细胞因子对皮肤屏障功能的影响的详细了解。 与公众健康相关：皮肤为环境中的有害成分提供了屏障，包括感染。特应性皮炎是一种皮肤过敏性疾病，会改变皮肤的屏障功能，增加过敏性炎症和感染。这项建议定义了屏障功能改变的机制，并检查了免疫系统与参与屏障功能的基因的相互作用。

DESCRIPTION (provided by applicant): Skin inflammation in Atopic Dermatitis (AD) patients includes dendritic cells, mast cells and T cells. Evidence for the function of several T helper subsets in AD exists both from patient samples and from mouse models. There is clearly a genetic component in disease; family history of allergy is one of the strongest predictors of AD, and mutations in the filaggrin (FLG) gene, a component of the Epidermal Differentiation Complex (EDC), have emerged as a predisposing factor for the development of AD. IL-4 and IL-13 promote atopic responses and decrease expression of a number of EDC genes, which are critical for barrier function. One of the primary questions that remain unanswered is whether the defect leading to AD is in the skin, in the atopic immune system, or whether disease requires defects in both systems. Central to answering this question is an understanding of how the immune system and the skin, particularly keratinocytes, interact at the molecular level. The overall goal of this Project is to define the interactions of cytokines that promote the development of atopic inflammation on keratinocyte gene expression and function, with the long-term goal of finding pathways that could be targeted for treatment of disease. Our hypothesis is that pro-allergic cytokines change the biology of keratinocytes and alter barrier function, facilitating increased allergen exposure. This hypothesis will be examined in two Aims that will examine the interactions of filaggrin mutations with increased Th2 immunity in a mouse model system, and define the function of STAT6 in regulating keratinocyte gene expression. Together, these studies will provide a detailed understanding of the effects of cytokines produced during allergic inflammation on skin barrier function. PUBLIC HEALTH RELEVANCE: Skin provides a barrier to harmful components in the environment including infection. Atopic Dermatitis, an allergic disease of the skin alters the barrier function of the skin and increases allergic inflammation and infection. This proposal defines the mechanism of altered barrier function and examines the interactions of the immune system with genes involved in barrier function.