Understanding the role of S. aureus agr virulence in atopic dermatitis

了解金黄色葡萄球菌 agr 毒力在特应性皮炎中的作用

• 批准号: 10631126
• 负责人: Masanori Matsumoto
• 金额: $ 9.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631126
• 关键词: Adult; Advisory Committees; Affect; Animal Model; Applications Grants; Atopic Dermatitis; Basic Science; Cellular biology; Child; Chronic; Clinical; Collaborations; Developed Countries; Development; Disease; Educational workshop; Epidermis; Flare; Foundations; Gene Expression; Genome; Goals; IL17 gene; Immunologist; Inflammation; Inflammatory; Interleukin-1 alpha; Interleukin-13; Interleukin-4; Knowledge; Laboratories; Left; Link; Manuscripts; Mediating; Mentors; Mentorship; Metabolism; Michigan; Modeling; Pathogenesis; Patients; Peptides; Phenols; Play; Preparation; Production; Regulator Genes; Relapse; Research; Research Activity; Research Personnel; Role; Skin; Solid; Staphylococcus aureus; Staphylococcus aureus infection; System; T-Lymphocyte; TSLP gene; Testing; Training; Training Activity; Type II Epithelial Receptor Cell; Universities; Up-Regulation; Virulence; Virulence Factors; Vitamin D Analog; Work; career; career development; chronic inflammatory skin; cytokine; cytotoxic; effective therapy; experience; genetic manipulation; human pathogen; insight; keratinocyte; meetings; mouse model; novel; novel strategies; novel therapeutics; pathogen; prevent; programs; quorum sensing; skill acquisition; skills; skin disorder; translational scientist; virulence gene

Project Summary Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15-30% of children and approximately 5% of adults in industrialized countries. However, effective treatments to prevent and treat this skin disease are lacking due in part to an incomplete understanding of the disease. The human pathogen Staphylococcus aureus has been linked to AD pathogenesis because more than 90% of AD patients are colonized in the lesional skin with the pathogen. Although S. aureus can produce multiple virulence factors, the mechanism by which S. aureus virulence contributes to AD remains unknown. Using a recently developed mouse model of epicutaneous S. aureus infection that resembles that observed in AD flares, we found that activation of the S. aureus accessory gene regulatory (Agr) quorum-sensing system induces the release of keratinocyte alarmins to trigger skin inflammation. We hypothesize that S. aureus Agr virulence factors play a critical role in skin inflammation associated with AD. We propose three Aims to test our hypotheses: 1) Use a novel AD mouse model to study the role of S. aureus in skin inflammation; 2) Determine the mechanism of S. aureus colonization in the skin and upregulation of Agr expression in lesional skin using the AD-like mouse model; 3) Examine the expression of S. aureus Agr virulence genes in lesional and non-lesional skin of AD patients and the function of AD- associated S. aureus in skin inflammation. These studies will provide critical insight into AD pathogenesis that will help the development of new approaches to treat AD. The candidate is a basic immunologist and Research Investigator at the University of Michigan. Under the guidance of his mentors and advisory team, he will acquire new knowledge and research expertise to test the hypothesis that both S. aureus Agr virulence and skin factors are important for triggering skin inflammation in AD using a newly developed AD model. The research proposed in his K01 application is a new scientific challenge in his career that offers the opportunities to integrate clinical and translational experience with his comprehensive training in basic science. Dr. Matsumoto's career development goals will be supported through close mentorship from an interdisciplinary team, advanced didactic coursework, attendance at professional meetings and workshops, participation in regular seminars, guidance in manuscript preparation and grant proposal development. This training and research activities will provide him with the necessary skills and experience needed to become a successful independent translational investigator.

项目总结