MECHANISMS OF DESMOSOME REGULATION IN SKIN DISEASE

皮肤病桥粒调控机制

• 批准号: 10614915
• 负责人: ANDREW P. KOWALCZYK
• 金额: $ 45.6万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614915
• 关键词: Adherens Junction; Adhesions; Adhesives; Autoantibodies; Autoimmune; Binding; Biological; Biophysics; Bulla; Cadherins; Calcium Signaling; Cell Communication; Cell Line; Cell membrane; Cell physiology; Cell surface; Cell-Cell Adhesion; Cells; Cellular biology; Complex; Data; Dermatitis; Desmosomes; Disease; Endocytosis; Endoplasmic Reticulum; Epithelium; Exposure to; Foundations; Functional disorder; Genetic Models; Germ Cells; Homeostasis; Hypersensitivity; Immunoglobulin G; Inherited; Intercellular Junctions; Intermediate Filaments; Lipids; Mechanics; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Membrane Proteins; Metabolic; Modeling; Morphology; Mutation; Nature; Null Lymphocytes; Outcome; Outcome Study; Pemphigus; Pemphigus Vulgaris; Play; Property; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Skin; Sterols; Structure; Syndrome; Testing; Transmembrane Domain; design; desmoglein III; experimental study; human disease; insight; keratinocyte; loss of function mutation; migration; molecular dynamics; mouse genetics; mutant; new therapeutic target; optical imaging; resilience; segregation; severe dermatitis, multiple allergies and metabolic wasting syndrome; skin disorder; therapeutic development; therapy development; wasting; wound healing

Desmosomes are adhesive intercellular junctions that play critical roles in epidermal homeostasis by mediating robust cell-cell adhesion and by modulating signaling pathways that regulate epidermal differentiation. The importance of desmosomes is highlighted by numerous autoimmune and inherited skin diseases that compromise desmosome function and cause epidermal fragility. These diseases include pemphigus vulgaris (PV), a severe autoimmune epidermal blistering disease caused by autoantibodies (IgG) directed against the desmosomal cadherin desmoglein-3 (Dsg3), and severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome caused by DSG1 loss of function mutations. Our previous studies of PV revealed that desmosomal proteins are associated with lipid rafts, and our recent findings indicate that a mutation in the Dsg1TMD that abrogates lipid raft association, compromises desmosome formation, and causes SAM syndrome. Lipid rafts are important for a variety of cellular functions, including signaling, endocytosis and membrane domain formation. The important role of lipid rafts in regulating Dsg function in different skin diseases underscores the importance of Dsg association with lipid rafts in normal desmosome function and epidermal homeostasis. We hypothesize that Dsg association with rafts is required for desmosome assembly, segregation from adherens junctions, and for Dsg adhesive and signaling activities necessary for epidermal homeostasis. The experiments outlined in this proposal are designed to reveal the raft targeting features of desmosomal cadherins, how raft association regulates desmosome and adherens junction membrane domain formation, and how loss of Dsg raft association leads to SAM syndrome. The outcome of these studies will produce fundamentally new conceptual models for desmosome regulation and will form a foundation for the treatment of skin diseases associated with loss of desmosome function.

桥粒是细胞间的粘附连接，在表皮细胞的生长和分化中起着重要作用。 通过介导稳固的细胞-细胞粘附和通过调节 调节表皮分化。桥粒的重要性被许多人强调， 自身免疫性和遗传性皮肤病，损害桥粒功能并引起表皮 脆弱这些疾病包括寻常天疱疮（PV），一种严重的自身免疫性表皮水疱， 由针对桥粒钙粘蛋白桥粒芯糖蛋白-3的自身抗体（IgG）引起的疾病 （Dsg 3），以及由Dsg 3引起的严重皮炎、多种过敏和代谢性消耗（SAM）综合征。 DSG 1功能缺失突变。我们以前对PV的研究表明，桥粒蛋白是 与脂筏相关，我们最近的研究结果表明，Dsg 1 TMD中的突变， 消除脂筏结合，损害桥粒形成，并引起SAM综合征。 脂筏对于多种细胞功能是重要的，包括信号传导、内吞作用和代谢。 膜结构域形成。脂筏在调节Dsg功能中的重要作用 皮肤疾病强调了Dsg与正常桥粒中脂筏的重要性 功能和表皮稳态。我们假设，Dsg与筏的关联是必要的， 桥粒组装，从粘附连接分离，以及Dsg粘附和信号传导 表皮稳态所必需的活动。该提案中概述的实验是 旨在揭示桥粒钙粘蛋白的筏靶向特征， 调节桥粒和粘附连接膜结构域的形成，以及Dsg筏的丢失如何影响细胞的增殖。 关联导致SAM综合征。这些研究的结果将产生全新的 桥粒调控的概念模型，并将形成皮肤治疗的基础 与桥粒功能丧失相关的疾病。