Thymic Stromal Lymphopoietin in Atopic Dermatitis

描述(申请人提供)：胸腺间质淋巴生成素(TSLP)在特应性皮炎(AD)中的作用最近被推测。在体外研究中，TSLP被证明可以激活CD11c+树突状细胞，这些树突状细胞随后能够耐受初始的CD4+T细胞，走向亲过敏的炎症状态。此外，AD皮损的活检组织中也发现高水平的TSLP表达。这些数据支持TSLP在包括AD在内的Th2介导的变态反应性疾病的发病机制中的关键早期作用。然而，还需要做更多的工作来更准确地确定它在过敏性疾病中的作用，并确定它是如何受到监管的。 目前的研究方案有两个目的。第一个是描述一种拟议的AD动物模型。我们已经开发出皮肤特异性TSLP过度表达的转基因小鼠，这证明了AD的所有特征发现。我们现在建议确定在这些小鼠中观察到的皮肤炎症所涉及的细胞类型和介质的特征，并确定TSLP在体内的致病作用，以便进一步建立这些小鼠作为有用的人类疾病模型。第二个目的是确定控制TSLP表达的顺式调控元件。

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.