Role of the Novel Matrix Metalloproteinase Epilysin in Atopic Dematitis

描述（由申请人提供）：A。表溶素（基质金属蛋白酶[MMPJ-28]）是一种由角质形成细胞和其他上皮细胞组成型表达的新型MMP。迄今为止，对epilysin的生理底物和体内功能知之甚少。我们现在有证据表明，在调节Th 2型过敏性炎症，如发生在哮喘和特应性皮炎（AD）的epilysin的潜在作用。在哮喘和AD小鼠模型（分别基于气道和表皮卵清蛋白激发）中，癫痫溶解素在急性炎症期间下调，然后似乎随时间增加。此外，与激发的野生型小鼠相比，缺乏癫痫溶解素的小鼠分别经历增加的肺部和皮肤炎症。表溶素也被TNF-α上调，TNF-α是过敏性炎症的重要介质。基于这些观察结果，我们假设，epilysin通过影响控制炎症的蛋白质的活性，在特应性炎症中起保护作用，并且其表达受炎性细胞因子环境的调节。AD是一种常见的慢性且通常使人衰弱的皮肤病，其发病机制和调节仍不完全清楚，因此缺乏疾病特异性治疗方法。我们的长期目标是阐明和定义一个潜在的关键监管方面的AD发病机制，即癫痫溶解素的作用，从而确定一个前瞻性的网站疾病干预。为此，我们建议定义epilysin在炎症中的作用，它的时间表达，以及它的调节。我们将使用AD的小鼠模型来评估癫痫溶解素在炎症过程中的时间表达。在特定的时间点，我们将通过RT-PCR确定epilysin的表达，并将其与组织学炎症程度、血清IgE以及细胞和细胞因子表型相关联。然后，我们将使用已建立的epilysin空小鼠比较上述炎症表型的epilysin的假定的调节功能的情况下所看到的。同时，我们将在体外研究监管方面。我们将研究用各种炎症细胞因子处理的培养角质形成细胞中epilysin的表达。我们还将采用荧光素酶测定法与建立的启动子构建体，以进一步表征推定的启动子调控结构域。B。特应性皮炎（AD）影响高达20%的学龄儿童，并有显着的身体，经济和心理社会影响。通过研究一种似乎在AD中起保护作用的分子，我们的目标是增加我们对AD如何调节的知识以及未来新疗法的可能性。

DESCRIPTION (provided by applicant): A. Epilysin (matrix metalloproteinase [MMPJ-28) is a novel MMP expressed constitutively by keratinocytes and other epithelial cell types. To date, little is known about epilysin's physiologic substrate(s) and in vivo function. We now have evidence suggesting a potential role for epilysin in modulating Th2-type allergic inflammation, as occurs in asthma and atopic dermatitis (AD). In both asthma and AD mouse models (based on airway and epicutaneous ovalbumin challenge, respectively), epilysin is downregulated during acute inflammation and then appears to increase over time. Furthermore, mice lacking epilysin experience increased lung and skin inflammation, respectively, compared to challenged wild-type mice. Epilysin is also upregulated by TNF-a, an important mediator of allergic inflammation. Based on these observations, we hypothesize that epilysin plays a protective role during atopic inflammation by affecting the activity of proteins that govern inflammationand that its expression is regulated by an inflammatory cytokine milieu. AD is a common, chronic, and often debilitating skin disease whose pathogenesis and regulation are still incompletely understood and for which disease-specific therapeutics are therefore lacking. Our long-term objective is to elucidate and define a potentially critical regulatory aspect of AD pathogenesis, namely the role of epilysin, thereby identifying a prospective site for disease intervention. To this end,we propose to define epilysin's role in inflammation, its temporal expression, and its regulation. We will use a mouse model of AD to evaluate the temporal expression of epilysin during inflammation. At particular time points, we will determine epilysin expression by RT-PCR and correlate this with degree of inflammation per histology, serum IgE,and cellular and cytokine phenotypes. We will then use established epilysin-null mice to compare the above inflammatory phenotypes to those seen in the absence of epilysin's putative regulatory function. Concurrently, we will examine regulatory aspects in vitro. We will examine epilysin expression in cultured keratinocytes treated with various inflammatory cytokines. We will also employ the luciferase assay with established promoter constructs to further characterize putative promoter regulatory domains. B. Atopic dermatitis (AD) affects up to 20% of school-aged children and has significant physical, economic, and psychosocial impact. By studying a molecule that appears to play a protective role in AD, we aim to increase our knowledge of how AD is regulated and the possibility for novel therapies in the future.