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剥脱性毒素 A（ETA）会破坏人体表皮大疱性脓疱病和葡萄球菌性烫伤皮肤综合症 (SSSS)，使受害者容易受到危及生命的感染和脱水。桥粒对于组织中的细胞：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丝锚定到细胞连接处，提供皮肤所需的机械强度，作为身体的第一道防线环境侮辱。先前的研究表明，ETA 可裂解桥粒糖蛋白 1 (Dsg1) 成分和浅表皮的主要钙粘蛋白。拟议的研究将确定 ETA 切割 Dsg1 导致 SSSS 的具体分子后果。特别是，毒素对桥粒成分的运输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，诱饵 Dsg1 胞外域将被评估为体外和表皮等效物中的 ETA 抑制剂。结果将提供更完整的理解 SSSS 发病机制的研究，并将确定治疗毒素介导疾病的新治疗靶点。