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: 8296974
• 负责人: NING LI
• 金额: $ 29.28万
• 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/8296974
• 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. PUBLIC HEALTH RELEVANCE: Pemphigus is a group of life-threatening autoimmune blistering diseases characterized by pathogenic autoantibodies that target epidermal desmogleins and cause skin blisters. The pathogenic mechanisms underlying how pemphigus autoantibodies lead to skin injury are not fully elucidated. In this application, we propose to investigate the role of proteinases in pemphigus skin blistering. The findings from this study should increase our understanding of the disease pathology and may lead to development of new treatments for the disease.

描述（由申请人提供）：寻常型天疱疮（PV）和落叶型天疱疮（PF）是潜在致命的自身免疫性皮肤水疱病。 PV 的特点是基底上水疱和针对桥粒芯糖蛋白 3 (Dsg3) 的 IgG 自身抗体，而 PF 的特点是角膜下水疱和针对 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 自身抗体引起表皮水疱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引起皮肤水泡的作用方式，以期产生可能有益于开发针对这些疾病的更好疗法的新知识。我们的中心假设是，蛋白水解参与了天疱疮的致病级联反应，并且基质金属蛋白酶 2 (MMP2) 通过蛋白水解裂解角质形成细胞的关键粘附分子，在表皮水疱形成的最后阶段发挥着关键作用。这一假设基于我们的新观察结果，即 MMP2 的药理学和遗传阻断可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。目标 1 是扩展我们对 MMP2 在诱导实验性天疱疮中关键作用的初步研究。目标 2 是证明模型小鼠和天疱疮患者皮肤中 MMP2 的上调和激活。目标 3 是研究 MMP2 如何促进天疱疮水疱形成。该提案的研究结果应显着增加我们对疾病病理学的理解，并确定这些疾病的新治疗靶点。 公共健康相关性：天疱疮是一组危及生命的自身免疫性水疱疾病，其特征是致病性自身抗体针对表皮桥粒芯蛋白并导致皮肤水疱。天疱疮自身抗体导致皮肤损伤的致病机制尚未完全阐明。在此应用中，我们建议研究蛋白酶在天疱疮皮肤起泡中的作用。这项研究的结果应该会增加我们对疾病病理学的了解，并可能导致开发出针对该疾病的新疗法。