Role of the matrix metalloproteinase in pemphigus autoantibody-mediated epidermal

描述(申请人提供)：寻常型天疱疮(PV)和叶型天疱疮(PF)是潜在的致命性自身免疫性皮肤水疱病。PV的特征是基底上水泡和抗桥粒芯糖蛋白3(Dsg3)的自身抗体，而PF的特征是角膜下水泡和抗DSG1的自身抗体。免疫球蛋白G被动转移小鼠模型证实了PV和PF自身抗体的致病性。然而，PF和PV自身抗体引起表皮起泡的机制尚不完全清楚。我们研究的总体目标是了解天疱疮自身抗体在导致皮肤起泡方面的作用模式，以努力产生新的知识，这些知识可能有助于开发更好的治疗这些疾病的方法。我们的中心假设是蛋白分解参与了天疱疮的病因级联反应，而基质金属蛋白酶2(MMP2)通过蛋白水解性裂解角质形成细胞的关键黏附分子在表皮水泡形成的最后阶段起关键作用。这一假设是基于我们新的观察结果，即MMP2的药理和基因阻断可以保护小鼠免受实验性天疱疮的侵袭。我们提出了三个具体目标来检验我们的假设。目的1是扩大我们对MMP2在实验性天疱疮诱导中的关键作用的初步研究。目的2证实MMP2在模型小鼠和天疱疮患者皮肤中的上调和激活。目的3是研究MMP2在天疱疮水泡形成中的作用。这项建议的发现将大大增加我们对疾病病理的了解，并确定这些疾病的新治疗靶点。

DESCRIPTION (provided by applicant): Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are potentially fatal autoimmune skin blistering diseases. While PV is characterized by suprabasilar blisters and IgG autoantibodies against desmoglein 3 (Dsg3), PF is characterized by subcorneal blisters and autoantibodies to Dsg1. The pathogenicity of PV and PF autoantibodies has been demonstrated by IgG passive transfer mouse models. However, the mechanism by which PF and PV autoantibodies cause epidermal blistering is not fully understood. The overall goal of our study is to understand the mode of action of pemphigus autoantibodies in causing skin blistering in an effort to generate new knowledge that may be beneficial in the development of better therapies for these diseases. Our central hypothesis is that proteolysis is involved in the pathogenic cascade of pemphigus, and that matrix metalloproteinase 2 (MMP2) plays a critical role in the final stage of epidermal blister formation via proteolytic cleavage of key adhesive molecules of keratinocytes. This hypothesis is based on our novel observations that pharmacologic and genetic blockade of MMP2 protects mice against experimental pemphigus. We propose three specific aims to test our hypothesis. Aim 1 is to extend our preliminary studies on the critical role of MMP2 in the induction of experimental pemphigus. Aim 2 is to demonstrate the upregulation and activation of MMP2 in the skin of model mice and pemphigus patients. Aim 3 is to investigate how MMP2 contributes to pemphigus blister formation. The findings from this proposal should significantly increase our understanding of the disease pathology and identify new therapeutic target for these diseases.