Microbial regulation of the keratinocyte AHR

项目摘要 近年来，人们对健康人体皮肤微生物群落的复杂性进行了研究 年，以及与炎症性皮肤病如特应性皮炎相关的特征。然而，在这方面， 介导微生物与皮肤共生的分子和生物化学机制并不完善 明白我们最近发现，稳态皮肤屏障功能，表皮分化和恢复， 都依赖于小鼠体内的微生物群。这些作用是由角质形成细胞芳基 碳氢化合物受体（AHR）。AHR是外源/有毒物质的配体依赖性异生物质受体 也已知其调节表皮分化、紧密连接/粘附和抗微生物先天性 免疫反应。本项目的目的是鉴定和表征AHR的微生物配体， 并测试它们在治疗皮肤屏障功能障碍和感染中的效用。表皮屏障功能障碍是 特应性皮炎的特征，特应性皮炎是一种常见的皮肤病，其特征是慢性和复发性，发痒，发炎， 皮肤损伤和微生物群失调。为了验证细菌介导AHR信号传导的假设， 为了促进皮肤屏障的完整性和防御，我们提出了三个目标。1)定义微生物机制 促进屏障修复角质形成细胞AHR调节; 2）建立微生物的药效学作用 AHR配体促进皮肤屏障功能和抗微生物防御;和3）评估微生物AHR配体 在治疗表皮屏障功能障碍和S.金黄色葡萄球菌感染的小鼠模型。这些调查结果 研究将提供新的，可访问的目标，以促进皮肤屏障功能和修复，同时推进 对皮肤宿主-微生物群相互作用的基本理解。

PROJECT SUMMARY The complexity of microbial communities inhabiting the healthy human skin have been illuminated in recent years, as well as signatures associated with inflammatory skin diseases such as atopic dermatitis. However, the molecular and biochemical mechanisms that mediate microbial symbiosis with the skin are not well understood. We recently found that homeostatic skin barrier function, epidermal differentiation, and recovery from injury are dependent on the microbiota in mice. These effects were mediated by the keratinocyte aryl hydrocarbon receptor (AHR). The AHR is a ligand-dependent xenobiotic receptor of foreign/toxic substances that is also known to regulate epidermal differentiation, tight junction/adhesion, and antimicrobial innate immune responses. The objective of this project is to identify and characterize microbial ligands of the AHR, and to test their utility in treating skin barrier dysfunction and infection. Epidermal barrier dysfunction is a key feature of atopic dermatitis, a common skin disorder characterized by chronic and relapsing, itchy, inflamed, skin lesions and dysbiotic microbiota. To test the hypothesis that commensal bacteria mediate AHR signaling to promote skin barrier integrity and defense, we propose three aims. 1) Define microbial mechanisms of keratinocyte AHR regulation that promote barrier repair; 2) Establish pharmacodynamic actions of microbial AHR ligands to promote skin barrier function and antimicrobial defense; and 3) Evaluate microbial AHR ligands in treatment of epidermal barrier dysfunction and S. aureus infection in murine models. Findings from these studies will provide novel, accessible targets to promote skin barrier function and repair, while advancing fundamental understanding of cutaneous host-microbiota interactions.