The mechanism of thymic stromal lymphopoietin overexpression by epithelial cells

描述（申请人提供）：哮喘和特应性皮炎是两种主要的过敏性疾病，分别是由肺部气道和皮肤的慢性炎症引起的。除了哮喘和特应性皮炎的临床和病理相似之外，这两种并发症经常发生在同一患者身上，这表明它们具有共同的病因，特别是在儿童时期。重要的是，最近的分子研究已经确定胸腺基质淋巴生成素（TSLP）是引起这两种疾病的共同启动因子。TSLP是一种上皮来源的il -7样细胞因子，能够激活树突状细胞介导的辅助性T - 2炎症，这是哮喘和特应性皮炎发病机制的核心。虽然TSLP与炎症和疾病的分子通路已被广泛研究，但刺激肺和皮肤上皮细胞过度表达TSLP的机制尚不完全清楚。目前的教条倾向于过敏原/病原体可能在引起上皮细胞TSLP过表达中起作用。研究认为，有缺陷的上皮屏障功能允许入侵因子直接接触和损伤上皮细胞，诱导它们释放TSLP作为次要效应。然而，我们最近的研究结果表明，异常屏障形成本身是诱导上皮细胞过度表达TSLP的有效刺激。因此，有趣的假设是，在需要功能性屏障之前，固有的上皮分化/屏障形成缺陷是无法正常分化的上皮过度表达TSLP的主要原因。为了验证这一假设，该项目将重点放在我们实验室广泛研究的模型器官上，即小鼠皮肤。提出的具体目标将研究(1)表皮分化/屏障形成缺陷（内在因素）如何在分子水平上导致TSLP过表达；(2)屏障功能障碍（外在因素）是否能够诱导具有短暂或慢性屏障缺陷的皮肤过度表达TSLP。这些目标的实现将扩展我们最近的发现，确定环境和遗传学在调节上皮TSLP过量产生中的作用，并确定介导这种作用的细胞自主方面的信号通路。最终，它将确定内在上皮缺陷在哮喘和特应性皮炎发展中的相对重要性，开辟一种新的治疗方法来治疗这些慢性疾病。超过2000万美国人患有哮喘，哮喘和特应性皮炎是影响儿童和成人的大多数慢性过敏性疾病。因此，对这些疾病进行更好的治疗将使一大群患者受益，并显著减轻医疗保健系统的负担。

DESCRIPTION (provided by applicant): Asthma and atopic dermatitis are the two major allergic diseases, which are caused by chronic inflammation affecting lung airways and skin, respectively. In addition to the clinical and pathological similarities between asthma and atopic dermatitis, both complications develop frequently in the same patient, suggesting a common etiology particularly during childhood. Importantly, the recent molecular studies have identified thymic stromal lymphopoietin (TSLP) as a common initiating factor causing both disorders. TSLP is an epithelial-derived IL-7-like cytokine capable of activating dendritic cell-mediated T helper 2 inflammation, which is central in pathogenesis of asthma and atopic dermatitis. Although the molecular pathways connecting TSLP to the inflammation and disease have been studied extensively, the mechanism stimulating lung and skin epithelial cells to overexpress TSLP is not fully understood. The current dogma favors the role that allergens/pathogens may play in causing epithelial TSLP overexpression. It argues that defective epithelial-barrier function allows the invading agents to directly contact and injure the epithelial cells, inducing them to release TSLP as a secondary effect. Our recent findings, however, demonstrated that aberrant barrier formation itself serves as a potent stimulus inducing TSLP overexpression by epithelial cells. Therefore, it is intriguing to hypothesize that intrinsic epithelial differentiation/barrier formation defects that precede the need for a functional barrier, are the primary cause of TSLP overexpression by the epithelia that fail to properly differentiate. To test this hypothesis, this project will focus on a model organ that is extensively studied in our lab, the mouse skin. The proposed specific aims will examine (I) how epidermal differentiation/barrier formation defects (intrinsic factors) cause TSLP overexpression at the molecular level and (II) if barrier dysfunction (extrinsic factor(s)) is able to induce TSLP overexpression by the skin that has a transient or chronic barrier defect. Achievement of these aims will extend our recent discovery, establishing the role of environment and genetics in regulating epithelial TSLP overproduction, also identifying the signaling pathway mediating the cell autonomous aspect of such an effect. Ultimately, it will determine the relative importance of intrinsic epithelial defects in the development of asthma and atopic dermatitis, opening up a novel therapeutic approach to treat these chronic diseases. More than 20 million Americans suffer from asthma, which together with atopic dermatitis account for the majority of chronic allergic diseases affecting children and adults. Thus, better treatment for these conditions will benefit a large group of patients and significantly reduce the burden on the healthcare system.