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: 7482134
• 负责人: ANDREW P. KOWALCZYK
• 金额: $ 38.25万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7482134
• 关键词: Adhesions; Adhesives; Amino Acids; Antibodies; Autoantibodies; Autoimmune Process; Biology; Bulla; Cadherins; Cell Adhesion Molecules; Cell surface; Cell-Cell Adhesion; Cells; Characteristics; Class; Complement; Complex; Couples; Cultured Cells; Cytokeratin filaments; Cytoplasmic Tail; Cytoskeletal Modeling; Desmosomes; Disease; Disruption; 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; Thinking; Work; armadillo proteins; base; desmoglein III; desmoplakin; human monoclonal antibodies; in vivo; in vivo Model; insight; keratinocyte; member; novel therapeutics; plakophilins; polypeptide D6; prevent; response; skin disorder; therapeutic target

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. Pemhigus 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 proposal 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. These studies will be complemented by in vivo models of disease to determine if agents that block PV IgG induced loss of adhesion in vitro can also block loss of adhesion in vivo. A panel of antibody reagents will be employed, including PV patient IgG, human monoclonal antibodies isolated 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 cause disease at the cellular level. 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.

天疱疮是一类破坏性的表皮起泡疾病，其中产生自身抗体 对抗皮肤和粘膜中存在的细胞-细胞粘附分子。天疱疮IgG靶标 桥粒，一种将角蛋白中间丝网络与强细胞间连接区域偶联的结构。 粘连在寻常型天疱疮（PV）中，自身抗体的主要靶点是桥粒芯糖蛋白-3（Dsg 3）， 粘附分子桥粒钙粘蛋白亚家族成员。本提案中概述的工作 研究寻常天疱疮患者IgG破坏细胞间粘附的机制。是 假设PV IgG通过引起Dsg 3从细胞表面内化而破坏桥粒， 导致桥粒不稳定和角质形成细胞粘附丧失。这个假设将使用一个 一系列体外细胞培养模型，采用细胞和分子方法来定义 PV IgG引起Dsg 3内化和桥粒解体的机制。这些研究将 揭示了介导Dsg 3内吞作用的细胞机制和途径，以及细胞质如何 桥粒的组分调节Dsg 3内化。这些研究将得到补充， 体内疾病模型，以确定在体外阻断PV IgG诱导的粘附丧失的药物是否也可以 阻断体内粘连丧失。将使用一组抗体试剂，包括PV患者IgG， 从患者分离的人单克隆抗体，和具有不同 致病活动的程度。这些试剂将用于揭示桥粒之间的关系 拆卸途径和抗体致病性谱，以确定天疱疮IgG如何引起疾病 在细胞水平上。这些研究旨在对基本的细胞机制产生新的见解 调节细胞-细胞粘附，并揭示用于治疗天疱疮的新治疗靶点， 其他以表皮脆弱为特征的皮肤病。