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，分别由慢性炎症影响肺部和皮肤引起。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间质淋巴生成素(TSLP)是导致这两种疾病的共同启动因素。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T辅助细胞2炎症，在哮喘和特应性皮炎的发病机制中起核心作用。尽管TSLP与炎症和疾病的分子通路已经被广泛研究，但刺激肺和皮肤上皮细胞过度表达TSLP的机制还不完全清楚。目前的教条倾向于过敏原/病原体可能在导致上皮TSLP过度表达中所起的作用。它认为，有缺陷的上皮屏障功能允许入侵者直接接触和损伤上皮细胞，诱导它们释放TSLP作为次要作用。然而，我们最近的发现表明，异常屏障形成本身是一种强大的刺激，可以诱导上皮细胞TSLP的过度表达。因此，有趣的是，假设固有的上皮分化/屏障形成缺陷先于功能屏障的需要，是未能正确分化的上皮过度表达TSLP的主要原因。为了验证这一假设，这个项目将专注于我们实验室广泛研究的一个模型器官--小鼠皮肤。拟议的特定目标将研究(I)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过度表达，以及(Ii)屏障功能障碍(外部因素(S))是否能够通过具有一过性或慢性屏障缺陷的皮肤诱导TSLP过度表达。这些目标的实现将扩展我们最近的发现，确立环境和遗传学在调节上皮TSLP过度生产中的作用，并确定介导这种影响的细胞自主方面的信号通路。最终，它将确定固有的上皮缺陷在哮喘和特应性皮炎发展中的相对重要性，开辟一种治疗这些慢性疾病的新方法。超过2000万美国人患有哮喘，加上特应性皮炎，这是影响儿童和成人的慢性过敏性疾病的主要原因。因此，对这些疾病进行更好的治疗将使一大批患者受益，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.