Mechanisms of Desmosome Regulation and Disassembly in the Skin Disease Pemphigus

皮肤病天疱疮中桥粒调节和分解的机制

• 批准号: 8303018
• 负责人: ANDREW P. KOWALCZYK
• 金额: $ 32.41万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303018
• 关键词: Adhesions; Adhesives; Amino Acids; Antibodies; Autoantibodies; Autoimmune Diseases; Biology; Bulla; Cadherins; Cell Adhesion Molecules; Cell Culture Techniques; Cell surface; Cell-Cell Adhesion; Cells; Characteristics; Couples; Cytokeratin filaments; Cytoplasmic Tail; Cytoskeletal Modeling; Desmosomes; Disease; Endocytosis; Exposure to; Functional disorder; Funding; Goals; Immunoglobulin G; In Vitro; Inborn Genetic Diseases; Individual; Intercellular Junctions; Intermediate Filaments; Keratin; Laboratories; Lead; Life; Mediating; Membrane Protein Traffic; Microscopy; Modeling; Molecular; Mucous Membrane; Mus; Pathogenicity; Pathway interactions; Patients; Pemphigus; Pemphigus Vulgaris; Phase; Play; Process; Proteins; Reagent; Regulation; Research Design; Role; Series; Signal Pathway; Skin; Structure; Tail; Testing; Therapeutic; Work; armadillo proteins; base; desmoglein III; desmoplakin; human monoclonal antibodies; insight; keratinocyte; member; new therapeutic target; novel therapeutic intervention; plakophilins; prevent; protein complex; response; skin disorder

DESCRIPTION (provided by applicant): Pemphigus is a class of devastating epidermal blistering diseases in which autoantibodies are generated against cell-cell adhesion molecules present in the skin and mucous membranes. Pemphigus IgG target desmosomes, a structure that couples the keratin intermediate filament network to regions of strong cell-cell adhesion. In pemphigus vulgaris (PV), the primary target of the autoantibodies is desmoglein-3 (Dsg3), a member of the desmosomal cadherin subfamily of adhesion molecules. The work outlined in this application investigates the mechanisms by which IgG from pemphigus vulgaris patients disrupts cell-cell adhesion. It is hypothesized that PV IgG disrupt desmosomes by causing Dsg3 internalization from the cell surface, leading to desmosome destabilization and loss of keratinocyte adhesion. This hypothesis will be tested using a series of in vitro cell culture models that employ cellular and molecular approaches to define the mechanisms by which PV IgG cause Dsg3 internalization and desmosome disassembly. These studies will reveal the cellular machinery and pathways that mediate Dsg3 endocytosis, and how cytoplasmic components of the desmosome regulate Dsg3 internalization. Furthermore, a panel of antibody reagents will be employed, including PV patient IgG, human monoclonal antibodies cloned from patients, and mouse monoclonal Dsg3 antibodies with varying degrees of pathogenic activity. These reagents will be used to reveal relationships between desmosome disassembly pathways and antibody pathogenicity profiles to determine how pemphigus IgG causes disease at the cellular level. RELEVANCE: These studies are designed to generate new insights into the basic cellular mechanisms that regulate cell-cell adhesion, and to expose new therapeutic targets for the treatment of pemphigus and other skin diseases characterized by epidermal fragility.

描述（由申请人提供）：天疱疮是一类破坏性表皮起泡性疾病，其中自身抗体产生对抗存在于皮肤和粘膜中的细胞粘附分子。天疱疮IgG靶向桥粒，一种将角蛋白中间丝网络偶联到强细胞-细胞粘附区域的结构。在寻常型天疱疮（PV）中，自身抗体的主要靶点是桥粒蛋白-3 (Dsg3)，它是黏附分子桥粒钙粘蛋白亚家族的一员。在本应用程序中概述的工作调查机制，IgG从寻常型天疱疮患者破坏细胞-细胞粘附。假设PV IgG通过引起Dsg3从细胞表面内化来破坏桥粒，导致桥粒不稳定和角化细胞粘附丧失。这一假设将通过一系列体外细胞培养模型进行验证，这些模型采用细胞和分子方法来确定PV IgG导致Dsg3内化和桥粒分解的机制。这些研究将揭示介导Dsg3内吞作用的细胞机制和途径，以及桥粒细胞质成分如何调节Dsg3内化。此外，将使用一组抗体试剂，包括PV患者IgG，从患者身上克隆的人单克隆抗体，以及具有不同程度致病活性的小鼠单克隆Dsg3抗体。这些试剂将用于揭示桥粒分解途径和抗体致病性之间的关系，以确定天疱疮IgG如何在细胞水平上引起疾病。相关性：这些研究旨在对调节细胞-细胞粘附的基本细胞机制产生新的见解，并为天疱疮和其他以表皮脆弱为特征的皮肤疾病的治疗提供新的治疗靶点。