Exfoliative toxin A and desmosomal adhesion in epidermis

剥脱性毒素A与表皮桥粒粘附

• 批准号: 7158275
• 负责人: Cory L Simpson
• 金额: $ 3.35万
• 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/7158275
• 关键词: Staphylococcus aureus; bacteria infection mechanism; bacterial toxicology; bacterial toxins; cadherins; cell adhesion; cell migration; intercellular connection; intermolecular interaction; keratinocyte; pathologic process; predoctoral investigator; skin disorder; tissue /cell culture

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：金黄色葡萄球菌分泌的剥脱性毒素 A (ETA) 会导致大疱性脓疱病和葡萄球菌烫伤皮肤综合征 (SSSS) 破坏人体表皮，使受害者容易受到危及生命的感染和脱水。桥粒对于承受压力的组织（例如表皮）中的细胞：细胞粘附至关重要。这些蛋白质复合物将中间丝锚定在细胞连接处，为皮肤提供必要的机械强度，使其成为人体抵御环境侵害的第一道防线。先前的研究表明，ETA 可裂解桥粒芯蛋白 1 (Dsg1)，桥粒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，该毒素对桥粒成分的运输和相互作用的影响将作为减少角质形成细胞粘附的机制进行研究；此外，诱饵 Dsg1 胞外域将在体外和表皮等效物中作为 ETA 抑制剂进行评估。这些结果将提供对 SSSS 发病机制的更全面的了解，并将确定治疗毒素介导疾病的新治疗靶点。