Role of keratinocyte-derived cytokines in epidermal injury and atopic dermatitis

 描述(由申请人提供)： 本研究的主要目的是对白介素33和白介素3是如何 33个受体参与了特应性皮炎的发病机制，这是一种经常使人虚弱的皮肤炎症性疾病，影响着包括退伍军人在内的1000多万美国人。细胞因子是包括角质形成细胞在内的多种细胞产生的一类重要的炎性蛋白。白介素33是一种由角质形成细胞和其他类型的细胞产生的细胞因子，与特应性皮炎和另一种常见的皮肤炎症性疾病牛皮癣有关。与大多数细胞因子不同的是，IL-33还在细胞核内具有细胞内功能 它可能调节基因的表达。这项工作将评估IL-33和IL-33受体调节Stat6VT转基因小鼠特应性皮炎样表型的机制(S)，这是一种T细胞依赖的小鼠疾病模型。这些研究还将扩大到特应性皮炎和牛皮癣患者。使用T1/ST2(即IL-33受体的配体特异性亚单位)基因敲除小鼠将有助于确定IL-33对Stat6VT小鼠特应性皮炎样表型的免疫调节作用是否由IL-33受体介导。将进行过继转移实验，以确定调节性T细胞是否以IL-33受体依赖的方式对Stat6VT小鼠的特应性皮炎样表型的免疫调节做出贡献。特应性皮炎和牛皮癣患者(和健康对照组)的皮肤来源的CD4T细胞将被分离出来，以研究IL-33对这些细胞产生效应细胞因子的影响。IL-33和IL-33受体在表皮屏障功能和角质形成细胞分化中的作用将在IL-33和T1/ST2基因敲除小鼠中进行评估。类似的研究将在使用人角质形成细胞的情况下进行，在角质形成细胞中，IL-33和IL-33受体的表达通过慢病毒系统进行调节，以强制和/或减弱IL-33和T1/ST2的表达。总之，该项目旨在促进对IL-33和IL-33受体如何参与特应性皮炎的理解，并将我们的研究扩展到牛皮癣，这是人类最常见的两种炎症性疾病。这些研究的最终目标是确定新的治疗目标，以改进对这些和其他常见皮肤炎症性疾病的治疗，从而改善退伍军人和其他患者群体的保健。

 DESCRIPTION (provided by applicant): The primary goal of this research is to gain novel insights into how Interleukin (IL)-33 and the IL 33 receptor are involved in the pathogenesis of atopic dermatitis, an often-debilitating inflammatory disease of the skin that affects over ten million Americans, including Veterans. Cytokines are an important class of inflammatory proteins produced by many cell types including keratinocytes. Interleukin 33 is a cytokine produced by keratinocytes and other cell types and is implicated in atopic dermatitis and another common inflammatory disease of the skin, psoriasis. Unlike most cytokines, IL-33 also has intracellular functions in the nucleus where it may regulate gene expression. This work will evaluate the mechanism(s) by which IL-33 and the IL-33 receptor regulate the atopic dermatitis-like phenotype in Stat6VT transgenic mice, a T cell-dependent mouse model of disease. These studies will also be extended to involve patients with atopic dermatitis and psoriasis. Use of T1/ST2 (i.e. the ligand-specific subunit of the IL-33 receptor) knockout mice will help determine if the immunoregulatory effects of IL-33 on the atopic dermatitis-like phenotype in Stat6VT mice are mediated by the IL-33 receptor. Adoptive transfer experiments will be performed to determine if regulatory T cells contribute to immunoregulation of the atopic dermatitis-like phenotype in Stat6VT mice in an IL-33 receptor-dependent manner. Skin-derived CD4+ T cells from patients with atopic dermatitis and psoriasis (and healthy controls) will be isolated to study the impact of IL-33 on effector cytokine production by these cells. The roles of IL-33 and the IL-33 receptor in epidermal barrier function and keratinocyte differentiation will be evaluated using IL-33 and T1/ST2 knockout mice. Similar studies will be performed with using human keratinocytes in which IL-33 and IL-33 receptor expression are modulated using lentiviral systems to force and/or attenuate expression of IL-33 and T1/ST2. In conclusion this project is designed to advance the understanding of how IL-33 and the IL- 33 receptor are involved in atopic dermatitis and extend our studies to psoriasis, two of the most common inflammatory diseases of humans. The ultimate goal of these investigations is to identify novel therapeutic targets to improve treatments of these and other common inflammatory diseases of the skin thereby improving healthcare for Veterans and other patient populations.