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: 10447488
• 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/10447488
• 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; Genes; Genome; Goals; Immunologist; Inflammation; Inflammatory; Interleukin-1 alpha; Interleukin-13; Interleukin-17; Interleukin-4; Knowledge; Laboratories; Left; Lesion; 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; base; 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; skills; skin disorder; skin lesion; translational scientist

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.

项目摘要 特应性皮炎（AD）是一种慢性炎症性皮肤病，影响15-30%的儿童， 在工业化国家，大约有5%的成年人。然而，有效的治疗方法，以防止和治疗 这种皮肤病缺乏部分原因是对这种疾病的不完全了解。人类 病原体金黄色葡萄球菌与AD发病机制有关，因为超过90%的AD 患者的病变皮肤中定植有病原体。虽然S.金黄色葡萄球菌可以产生多种 毒力因子，S.金黄色葡萄球菌的毒力对AD的贡献仍然未知。使用 最近开发的表皮S.金黄色葡萄球菌感染，类似于在AD中观察到的感染 耀斑时，我们发现S.金黄色葡萄球菌辅助基因调节（Agr）群体感应系统 诱导角化细胞警报素的释放以引发皮肤炎症。我们假设S.金黄色 Agr毒力因子在与AD相关的皮肤炎症中起关键作用。 我们提出了三个目的来验证我们的假设：1）使用一种新的AD小鼠模型来研究S。 金黄色葡萄球菌在皮肤炎症中的作用机制;皮肤中的金黄色葡萄球菌定植， 使用AD样小鼠模型在病变皮肤中Agr表达的上调; 3）检查Agr表达， 色葡萄AD患者皮损和非皮损皮肤中的金黄色葡萄球菌Agr毒力基因以及AD- 相关S.金黄色葡萄球菌皮肤炎症。这些研究将为AD的发病机制提供重要的见解 这将有助于开发治疗AD的新方法。 候选人是密歇根大学的基础免疫学家和研究调查员。下 他的导师和顾问团队的指导下，他将获得新的知识和研究专长，以测试 假设S.金黄色葡萄球菌Agr毒力和皮肤因子对于触发皮肤炎是重要的。 使用新开发的AD模型研究AD中的炎症。他在K 01申请中提出的研究是一项 他的职业生涯中新的科学挑战，提供了整合临床和转化的机会 他在基础科学方面的综合训练经验。松本博士的职业发展目标 将通过跨学科团队的密切指导，先进的教学课程， 出席专业会议和讲习班，参加定期研讨会， 编写手稿和编写赠款提案。这些培训和研究活动将提供 他与必要的技能和经验需要成为一个成功的独立翻译 调查员