Exfoliative toxin A and desmosomal adhesion in epidermis

剥脱性毒素A与表皮桥粒粘附

基本信息

批准号：
7682888
负责人：
Cory L Simpson
金额：
$ 5.66万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7682888
关键词：
Adhesions Adhesives Antibodies Binding Biochemical Biological Assay Biotin Bulla Cadherins Canis familiaris Cell-Cell Adhesion Cells Cleaved cell Co-Immunoprecipitations Complex Cultured Cells Cytoplasm Cytoskeletal Modeling Dehydration Desmosomes Disease Dominant-Negative Mutation Dose Epidermis Event Exfoliative Toxins Human Immunofluorescence Microscopy Impetigo In Vitro Infection Intermediate Filaments Label Life Link Mechanics Mediating Membrane Modeling Molecular Pathogenesis Play Protein Family Proteins RNA Interference Research Resistance Role Signal Transduction Skin Solubility Staphylococcal Scalded Skin Syndrome Staphylococcus aureus Stress Syndrome Targeted Toxins Therapeutic Tissues Toxin Work armadillo proteins desmoglein 1 desmoplakin improved inhibitor/antagonist keratinocyte knock-down monolayer mutant new therapeutic target pathogen plakoglobin plakophilins protein complex protein transport research study response therapeutic target trafficking

项目摘要

Exfoliative toxin A (ETA) secreted by Staphylococcus aureus causes destruction of human epidermis in bullous impetigo and Staphylcoccal Scalded Skin Syndrome (SSSS), which renders victims vulnerable to life-threatening infections and dehydration. Desmosomes are crucial for cell:cell adhesion in tissues enduring stress, such as the epidermis. These protein complexes anchor intermediate filaments to celhcell junctions, providing the mechanical strength necessary for the skin to serve as the body's first line of defense against environmental insults. Previous work has shown that ETA cleaves desmoglein 1 (Dsg1), a desmosome component and the predominant cadherin of the superficial epidermis. The proposed research will determine the specific molecular consequences of Dsg1 cleavage by ETA that contribute to SSSS. In particular, the toxin's effects on trafficking of and interactions among desmosomal components will be investigated as mechanisms reducing adhesion in keratinocytes; as well, a decoy Dsg1 ectodomain will be evaluated as an ETA inhibitor in vitro and in epidermal equivalents. The results will provide a more complete understanding of SSSS pathogenesis and will identify novel therapeutic targets for treatment of a toxin-mediated disease.

金黄色葡萄球菌分泌的去角质毒素A（ETA）会导致人类表皮破坏大胆的盗窃和葡萄球菌烫伤皮肤综合征（SSSS），使受害者容易受到伤害威胁生命的感染和脱水。脱骨小体对于细胞：持续组织中的细胞粘附至关重要压力，例如表皮。这些蛋白质复合物将中间细丝锚定在celhcell连接处，提供皮肤作为人体对防御的第一道防御所必需的机械强度环境侮辱。先前的工作表明，ETA裂解Desmoglein 1（DSG1），一个脱粒体表皮表皮的成分和主要的钙粘蛋白。拟议的研究将确定 DSG1通过ETA裂解的特定分子后果会导致SSSS。特别是毒素对脱染色体成分之间的贩运和相互作用的影响将被研究为减少角质形成细胞粘附的机制；同样，将将诱饵DSG1胞外域评估为 ETA抑制剂体外和表皮当量。结果将提供更完整的理解 SSS的发病机理，并将确定用于治疗毒素介导的疾病的新型治疗靶标。