Exfoliative toxin A and desmosomal adhesion in epidermis

剥脱性毒素A与表皮桥粒粘附

• 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
• 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

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表皮剥脱毒素A（ETA）可破坏人体表皮， 大疱性脓疱病和葡萄球菌烫伤样皮肤综合征（SSSS），使受害者容易受到 危及生命的感染和脱水桥粒对于组织中细胞：细胞粘附的持久性至关重要 压力，如表皮。这些蛋白质复合物将中间丝锚在细胞连接处， 为皮肤提供必要的机械强度，作为身体的第一道防线， 环境侮辱。以前的研究表明，ETA切割桥粒糖蛋白1（Dsg 1）， 上皮细胞是表皮的主要成分和主要的钙粘蛋白。这项研究将确定 ETA切割Dsg 1导致SSSS的特定分子后果。特别是 毒素对桥粒组分的运输和相互作用的影响将被研究， 降低角质形成细胞中粘附的机制;同样，诱饵Dsg 1胞外域将作为 体外和表皮等同物中的ETA抑制剂。结果将提供一个更完整的了解 SSSS发病机制的研究，并将确定用于治疗毒素介导的疾病的新的治疗靶点。