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IL-13 Atopic Dermatitis and Its Relationship with the Development of Asthma

IL-13 特应性皮炎及其与哮喘发生的关系

基本信息

批准号：
8727188
负责人：
TAO ZHENG
金额：
$ 8.16万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727188
关键词：
IL 13 Atopic Dermatitis Its

项目摘要

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) has been proposed as the cutaneous manifestation of a systemic disorder that also gives rise to asthma and allergic rhinitis, the so-called "atopic march". AD and other atopic disorders have an overlapping pathogenesis and genetic basis. In addition, AD and asthma share some common immunological features, including elevated IgE, peripheral and lesional eosinophilia, Th2 cytokine elevation, epithelial dysfunction and similar allergenic triggers. Th2 inflammation is an important component in the pathogenesis of both asthma and AD. Interleukin-13, a major Th2 cytokine, is believed to be involved in the pathogenesis of AD. However the precise molecular mechanisms underlying AD still remain elusive and the relationship between AD and asthma is poorly understood. We have recently developed an externally regulatable overexpression transgenic model system in which IL-13 is selectively expressed in the murine skin. In our preliminary studies, expression of IL-13 in the skin causes a chronic pruritic inflammatory skin disease with many characteristics closely resembling those of human atopic dermatitis. Many proinflammatory cytokines are highly upregulated, including IL-17 and TSLP, in the skin. IL-13-induced chronic dermatitis causes a systemic Th2-prone environment. Moreover, IL-13-induced dermatitis is associated with increased pulmonary inflammation, mucus metaplasia and airway hyperresponsiveness to allergen challenges, suggesting that IL-13 induced AD predisposes to an asthma phenotype. From these studies, we hypothesized that IL-13 plays an important role in the pathogenesis of atopic dermatitis and IL-13-induced atopic dermatitis leads to the development of asthma. In this application, we propose to: (1) Further characterize the skin-specific IL-13 transgenic model of AD and define the downstream cellular, molecular, and immunological mechanisms of IL-13-induced AD; (2) Determine if IL-13-induced AD leads to increased susceptibility to the development of allergic phenotype in the lung and the immunological mechanisms that underlie the progression from AD to asthma; and (3) Define the role of TSLP in IL-13 induced AD and in increased susceptibility to the development of allergic response to allergens in the lung. These studies will provide better understanding of the role of IL-13 in the pathogenesis of AD and its relationship with the development of asthma and the cellular and molecular mechanisms underlying these related disorders.

描述（由申请人提供）：特应性皮炎（AD）被认为是一种全身性疾病的皮肤表现，也可引起哮喘和过敏性鼻炎，即所谓的“特应性进行曲”。AD和其他特应性疾病具有重叠的发病机制和遗传基础。此外，AD和哮喘具有一些共同的免疫学特征，包括IgE升高、外周和病变嗜酸性粒细胞增多、Th 2细胞因子升高、上皮功能障碍和类似的过敏原触发因素。Th 2炎症是哮喘和AD发病机制中的重要组成部分。白细胞介素-13是一种主要的Th 2细胞因子，被认为参与AD的发病机制。然而，AD的确切分子机制仍然是难以捉摸的，AD和哮喘之间的关系知之甚少。我们最近开发了一种外部可调节的过表达转基因模型系统，其中IL-13在小鼠皮肤中选择性表达。在我们的初步研究中，IL-13在皮肤中的表达导致慢性皮炎性炎症性皮肤病，其许多特征与人类特应性皮炎的特征非常相似。许多促炎细胞因子在皮肤中高度上调，包括IL-17和TSLP。IL-13诱导的慢性皮炎导致全身性Th 2倾向环境。此外，IL-13诱导的皮炎与增加的肺部炎症、粘液化生和气道对变应原激发的高反应性相关，表明IL-13诱导的AD易患哮喘表型。从这些研究中，我们假设IL-13在特应性皮炎的发病机制中起重要作用，并且IL-13诱导的特应性皮炎导致哮喘的发展。在本申请中，我们提出：（1）进一步表征AD的皮肤特异性IL-13转基因模型，并确定IL-13诱导的AD的下游细胞、分子和免疫学机制;（2）确定IL-13诱导的AD是否导致对肺中变应性表型的发展的易感性增加，以及AD进展为哮喘的免疫学机制;（3）明确TSLP在IL-13诱导的AD中的作用以及在肺中对变应原的变态反应的易感性增加中的作用。这些研究将有助于更好地了解IL-13在AD发病机制中的作用及其与哮喘发展的关系以及这些相关疾病的细胞和分子机制。