Cytokine regulation of skin barrier function

描述（由申请方提供）：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均存在几种辅助性T细胞亚群在AD中的功能的证据。疾病中显然存在遗传成分;过敏家族史是AD的最强预测因子之一，并且表皮分化复合物（EDC）的组成部分聚丝蛋白（FLG）基因的突变已成为AD发展的诱发因素。IL-4和IL-13促进特应性反应并降低许多EDC基因的表达，这些基因对屏障功能至关重要。一个仍然没有答案的主要问题是导致AD的缺陷是否在皮肤中，在特应性免疫系统中，或者疾病是否需要两个系统的缺陷。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，长期目标是找到可以靶向治疗疾病的途径。我们的假设是，促过敏细胞因子改变角质形成细胞的生物学和改变屏障功能，促进增加过敏原暴露。这一假设将在两个目标中进行检验，这两个目标将检验聚丝蛋白突变与小鼠模型系统中增加的Th 2免疫力的相互作用，并定义STAT 6在调节角质形成细胞基因表达中的功能。总之，这些研究将提供一个详细的了解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。 公共卫生相关性：皮肤为环境中的有害成分（包括感染）提供了屏障。特应性皮炎是一种皮肤过敏性疾病，它改变了皮肤的屏障功能，增加了过敏性炎症和感染。该提案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.