Function of Desmoglein 1/Pemphigus Foliaceus Antigen

桥粒芯糖蛋白 1/天疱疮叶状疱疹抗原的功能

• 批准号: 7497958
• 负责人: Kathleen Janee Green
• 金额: $ 41.74万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497958
• 关键词: Actins; Adhesions; Adhesives; Affect; Antibodies; Autoantibodies; Bacterial Antibodies; Bacterial Toxins; Binding; Biochemistry; Biological; Biomimetics; Cadherins; Cell Adhesion Molecules; Cell Survival; Cell membrane; Cells; Complex; Coupled; Cutaneous; Cytoskeleton; Data; Desmosomes; Disease; Ensure; Epidermis; Etiology; Family; Family Dasypodidae; Family member; Foundations; Funding; Gene Family; Gene Mutation; Human; In Vitro; Intercellular Junctions; Intermediate Filaments; Knowledge; Left; Life; Maps; Mediating; Microtubules; Modeling; Molecular; Morphogenesis; Mus; Organelles; Palmoplantar Keratosis; Pathway interactions; Pattern; Pemphigus; Personal Satisfaction; Process; Production; Protein Analysis; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stratum Basale; Surface; Testing; Therapeutic Intervention; Time; Tissues; Transcend; Work; armadillo proteins; cellular imaging; desmocollin; desmoglein; desmoglein 1; human disease; in vivo; keratinocyte; novel; plakoglobin; plakophilins; protein protein interaction; research study; response; sensor; skin disorder; spatiotemporal; stoichiometry; tool; trafficking

DESCRIPTION (provided by applicant): Desmogleins (Dsgs) and desmocollins (Dscs) belong to a family of Ca2+dependent adhesion molecules known as cadherins, which cooperate to make up the adhesive core of intercellular junctions called desmosomes. Functional inactivation by a variety of insults, including autoimmune antibodies, bacterial toxins and gene mutations leads to human skin disease. Unfortunately, our understanding of the molecular etiology of these disorders is hampered by a lack of fundamental knowledge about the mechanisms by which desmosomal cadherins assemble into adhesion-competent organelles and the molecular machinery that drives this process. Further, the diversity of desmosomal cadherin family members within complex tissues, suggests that they may have functions that transcend their roles in intercellular adhesion. Indeed, our work suggests that the Dsg1 is required for the morphogenesis of epidermis in a manner that does not require its adhesive domain. It is our hypothesis that desmosomal cadherins have both adhesion-dependent and -independent functions that are coordinated during epidermal morphogenesis, differentiation and remodeling. Towards elucidating these functions and the molecular machinery that controls them, we propose: 1) To determine the mechanism of desmosomal cadherin trafficking in living keratinocytes and how Dsgs and Dscs cooperate to establish the adhesive interface, through a combination of live cell imaging and biochemistry coupled with mutational analysis of exocytic machinery. Novel biomimetic surfaces will be generated as functional platforms for evaluating requirements for adhesion and the ability of pathogenic pemphigus antibodies to inhibit adhesion and downstream cellular responses, 2) To determine the mechanism by which armadillo proteins regulate desmosomal cadherin assembly and adhesive function in conjunction with the cytoskeleton, by mutational analysis of protein interactions coupled with functional assessment of the linkage using novel micromechanical sensors, 3) To determine the function of Dsg1 and associated armadillo proteins in epidermal morphogenesis using in vitro, organotypic and mouse grafting models. These experiments promise to provide a model for the human disease striate palmoplantar keratoderma caused by loss of Dsg1, and will lay a foundation for developing treatments for skin diseases that target desmoglein function.

描述(申请人提供)：桥粒蛋白(Desmoglein，DGs)和桥粒蛋白(Desmocolin，DSCs)属于钙离子依赖的黏附分子家族，称为钙粘附素，它们共同组成称为桥粒的细胞间连接的黏附核心。包括自身免疫抗体、细菌毒素和基因突变在内的各种侮辱导致的功能失活会导致人类皮肤病。不幸的是，我们对这些疾病的分子病因学的理解受到了阻碍，因为我们缺乏关于桥粒钙粘附素组装成具有黏附能力的细胞器的机制以及驱动这一过程的分子机制的基础知识。此外，复杂组织中桥粒钙粘附素家族成员的多样性表明，它们可能具有超越其在细胞间黏附中的作用的功能。事实上，我们的工作表明DSG1对于表皮的形态发生是必需的，而不需要它的粘附域。我们的假设是，桥粒钙粘附素在表皮形态发生、分化和重塑过程中既具有黏附依赖性功能，又具有非黏附依赖性功能。为了阐明这些功能和控制它们的分子机制，我们建议：1)通过活细胞成像和生物化学结合胞外机制的突变分析，确定桥粒钙粘附素在活的角质形成细胞中运输的机制，以及DGs和DSCs如何合作建立黏附界面。将产生新的仿生表面作为功能平台，用于评估黏附要求以及致病天疱疮抗体抑制黏附和下游细胞反应的能力；2)通过对蛋白质相互作用的突变分析以及使用新型微机械传感器对连接的功能评估，确定犰螂蛋白调节桥粒钙粘附素组装和黏附功能与细胞骨架的机制；3)使用体外、器官型和小鼠移植模型确定DSG1和相关的Aradillo蛋白质在表皮形态发生中的功能。这些实验有望为由DSG1缺失引起的人类疾病纹状掌跖角化病提供一个模型，并将为开发针对桥粒蛋白功能的皮肤病治疗方法奠定基础。