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.

项目概要 特应性皮炎 (AD) 是一种慢性炎症性皮肤病，影响 15-30% 的儿童和儿童 工业化国家大约 5% 的成年人。然而，有效的治疗方法可以预防和治疗 这种皮肤病的缺乏部分是由于对该疾病的不完全了解。人类 病原体金黄色葡萄球菌与 AD 发病机制有关，因为 90% 以上的 AD 患者的病灶皮肤上有病原体定植。尽管金黄色葡萄球菌可以产生多种 毒力因素，金黄色葡萄球菌毒力导致 AD 的机制仍不清楚。使用 最近开发的表皮金黄色葡萄球菌感染小鼠模型，类似于 AD 中观察到的模型 耀斑，我们发现金黄色葡萄球菌辅助基因调节（Agr）群体感应系统的激活 诱导角质形成细胞警报素的释放，引发皮肤炎症。我们假设金黄色葡萄球菌 Agr 毒力因子在 AD 相关皮肤炎症中发挥着关键作用。 我们提出三个目标来检验我们的假设：1）使用新型 AD 小鼠模型来研究 S. 皮肤炎症中的金黄色葡萄球菌； 2) 确定金黄色葡萄球菌在皮肤中定植的机制和 使用 AD 样小鼠模型上调病变皮肤中的 Agr 表达； 3）检查表达式 AD患者皮损和非皮损皮肤中金黄色葡萄球菌Agr毒力基因的变化及其功能 皮肤炎症中相关的金黄色葡萄球菌。这些研究将为 AD 发病机制提供重要见解 这将有助于开发治疗 AD 的新方法。 该候选人是密歇根大学的基础免疫学家和研究研究员。下 在导师和顾问团队的指导下，他将获得新的知识和研究专业知识来测试 金黄色葡萄球菌 Agr 毒力和皮肤因素对于触发皮肤病都很重要的假设 使用新开发的 AD 模型来治疗 AD 炎症。他的 K01 申请中提出的研究是 他职业生涯中的新科学挑战提供了整合临床和转化的机会 受过基础科学综合训练的经验。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、指导 手稿准备和赠款提案制定。此次培训和研究活动将提供 他拥有成为一名成功的独立翻译人员所需的必要技能和经验 研究者。