Role of the Novel Matrix Metalloproteinase Epilysin in Atopic Dematitis

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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.