Role of the matrix metalloproteinase in pemphigus autoantibody-mediated epidermal

基质金属蛋白酶在天疱疮自身抗体介导的表皮中的作用

• 批准号: 8664737
• 负责人: NING LI
• 金额: $ 29.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664737
• 关键词: Acantholysis; Adhesives; Affinity; Antigen Targeting; Autoantibodies; Autoimmune Process; Binding; Biopsy; Bulla; Cell Culture Techniques; Cells; Cleaved cell; Data; Development; Disease; Epidermis; Gelatinase A; Genetic; Goals; Head; Human; Immunofluorescence Immunologic; Immunoglobulin G; In Vitro; Indium; Injury; Knowledge; Laboratories; Lead; Life; Matrix Metalloproteinases; Mediating; Mus; Pathogenicity; Pathology; Patients; Pemphigus; Pemphigus Vulgaris; Peptide Hydrolases; Play; Protease Inhibitor; Proteolysis; Recombinants; Relative (related person); Resistance; Role; Sampling; Serum; Skin; Staging; Testing; Up-Regulation; Wild Type Mouse; base; desmoglein; desmoglein III; in vitro Assay; inhibitor/antagonist; keratinocyte; mouse model; new therapeutic target; novel; proteinase In; research study; response

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.

描述（由申请人提供）：寻常型天疱疮（PV）和叶状天疱疮（PF）是潜在致命的自身免疫性皮肤起泡疾病。PV的特征是基底上水泡和抗粘连蛋白3 （Dsg3）的IgG自身抗体，而PF的特征是角膜下水泡和抗Dsg1的自身抗体。PV和PF自身抗体的致病性已通过IgG被动转移小鼠模型得到证实。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引起皮肤起泡中的作用模式，以努力产生新的知识，这可能有助于开发更好的治疗这些疾病的方法。我们的主要假设是，蛋白水解参与了天疱疮的致病级联反应，基质金属蛋白酶2 （MMP2）通过蛋白水解裂解角化细胞的关键粘附分子，在表皮水疱形成的最后阶段起关键作用。这一假设是基于我们的新观察，即MMP2的药理学和遗传阻断可以保护小鼠免受实验性天疱疮的侵害。我们提出三个具体目标来检验我们的假设。目的1是扩展我们对MMP2在实验性天疱疮诱导中的关键作用的初步研究。目的2是证明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如何促进天疱疮水疱的形成。这一发现将显著增加我们对疾病病理的认识，并为这些疾病找到新的治疗靶点。