Thymic Stromal Lymphopoietin in Atopic Dermatitis

描述（由申请人提供）：最近推测胸腺基质淋巴细胞生成素（TSLP）在特应性皮炎（AD）中的作用。在体外研究中，TSLP显示出激活CD11c+树突细胞，其随后能够耐受幼稚CD4+ T细胞朝向促过敏性炎症特征。此外，发现AD病变的活检表达高水平的TSLP。这些数据支持TSLP在包括AD在内的Th2介导的过敏性疾病的发病机制中的关键早期作用。然而，需要做进一步的工作来更精确地定义它在过敏性疾病中的作用，并确定它是如何调节的。 本研究计划有两个目的。第一个是表征AD的拟议动物模型。我们已经开发了皮肤特异性TSLP过表达的转基因小鼠，这证明了AD的所有特征性发现。我们现在建议表征这些小鼠中观察到的皮肤炎症中涉及的细胞类型和介质，并定义TSLP在体内的致病作用，以进一步建立这些小鼠作为人类疾病的有用模型。第二个目的是表征控制TSLP表达的顺式调节元件。

DESCRIPTION (provided by applicant): A role for thymic stromal lymphopoietin (TSLP) in atopic dermatitis (AD) has recently been postulated. In in vitro studies, TSLP was shown to activate CD11c+ dendritic cells, which were subsequently able to tolerize naive CD4+ T cells towards a pro-allergic inflammatory profile. In addition, biopsies of AD lesions were found to express high levels of TSLP. These data support a key early role for TSLP in the pathogenesis of Th2-mediated allergic disease including AD. However, further work needs to be done to define more precisely its role in allergic disease and also to determine how it is regulated. The present research proposal has two aims. The first is to characterize a proposed animal model of AD. We have already developed transgenic mice with skin-specific TSLP overexpression, which demonstrate all of the characteristic findings of AD. We now propose to characterize the cell types and mediators involved in the skin inflammation observed in these mice and to define the pathogenetic role of TSLP in vivo in order to further establish these mice as a useful model of human disease. The second aim is to characterize the cis-regulatory elements that control expression of TSLP.