Decoding microbial-Aryl Hydrocarbon Receptor interactions at the skin barrier interface

项目总结 有效的表皮渗透性屏障(EPB)保护皮肤免受脱水、发炎、早熟 衰老、环境暴露和感染。特应性皮肤屏障功能障碍是特应性疾病的重要特征 皮炎，以及包括牛皮癣、粉刺和酒渣鼻在内的多种皮肤病。一个基本的和 全面了解动态平衡屏障功能的调节机制是有效预防 并管理障碍异常。EPB功能驻留在皮肤表皮，它是各种 微生物群落。微生物群被认为是皮肤屏障的一个功能单位。皮肤 生态系统不断受到外部曝光体的挑战，包括紫外线(UVR)、空气 污染物和过敏原。对于屏障防御和动态平衡至关重要的是识别 外部信号并帮助识别有益(例如，共生微生物)和有害(例如，污染物， 病原体)调节屏障防御的外源生物。最近，我证明了共生微生物 通过激活异物感受器芳香来调节皮肤的表皮分化和屏障通透性 烃受体(AHR)。然而，共生微生物调控EPB的机制是通过 AHR在动态平衡下，以及在存在诸如UVR等环境侮辱的情况下，尚未被探索。中环 这一建议的假设是通过调节AHR-共生相互作用来调节上皮反应 可以改变屏障的渗透性。该项目通过整合转录组学来利用“多组学”方法， 元基因组学和代谢组学，以了解皮肤屏障修复中宿主-微生物区系的相互作用。在目标1中，我 将识别来自可激活AHR的合成共生群落的微生物信号。这些研究将 导致鉴定可用于针对屏障疾病中的AHR的微生物配体。在《目标2》中，我将测试 共生微生物组在抗紫外线屏障损伤中的作用及应用多组学 在AHR信号背景下表征微生物组-宿主-UV相互作用组的方法。这些研究 将提供一个框架来产生利用对环境-宿主-微生物组的理解的治疗方法 互动。在K99阶段，我将接受代谢组学方面的培训，以识别微生物代谢物。这就做 接受生物信息学和系统生物学方法方面的高级培训，重点是将 组学数据集。宾夕法尼亚大学出色的培训环境，加上 我组建的优秀的咨询委员会，将极大地促进我在指导阶段的研究。 以及开始我的职业生涯所需的技能，以了解微生物组宿主的角色- 环境在调节皮肤屏障修复中的作用。

PROJECT SUMMARY An effective epidermal permeability barrier (EPB) protects the skin from dehydration, inflammation, premature aging, environmental exposure, and infection. Epidermal barrier dysfunction is an important feature of atopic dermatitis, as well as numerous skin diseases including psoriasis, acne, and rosacea. A fundamental and holistic understanding of mechanisms regulating homeostatic barrier function is essential to effectively prevent and manage barrier abnormalities. The EPB function resides in the skin epidermis, which is home to diverse microbial communities. The microbiome is recognized as a functional unit of the skin barrier. The skin ecosystem is continuously challenged by the external exposome that includes ultraviolet radiation (UVR), air pollutants and allergens. Critical for the barrier defense and homeostasis are xenobiotic sensors that recognize external signals and help identify beneficial (e.g., commensal microbes) from harmful (e.g., pollutants, pathogens) xenobiotics to regulate barrier defenses. Recently, I have demonstrated that commensal microbes regulate epidermal differentiation and barrier permeability of the skin by activating xenobiotic sensor, the aryl hydrocarbon receptor (AHR). However, the mechanisms by which commensal microbes regulate EPB through AHR under homeostasis, and in presence of environmental insults such as UVR are unexplored. The central hypothesis of this proposal is that tuning of epithelial responses by modulating AHR-commensal interactions can alter barrier permeability. This project utilizes ‘multi-omics’ approaches by integrating transcriptomics, metagenomics, and metabolomics to understand host-microbiota interactions in skin barrier repair. In Aim 1, I will identify microbial signals from a synthetic commensal community that can activate AHR. These studies will lead to identification of microbial ligands that can be used to target AHR in barrier diseases. In Aim 2, I will test contributions of commensal microbiome in protecting against UV-induced barrier damage and use multiomics approaches to characterize microbiome-host-UV interactome in the context of AHR signaling. These studies will provide a framework to generate therapies that leverage understanding of environmental-host-microbiome interactions. During the K99 phase, I will be trained in metabolomics to identify microbial metabolites. I will receive advanced training in bioinformatics and systems biology approaches that focus on integrating multiple omics datasets. The outstanding training environment at the University of Pennsylvania coupled with the excellent advisory committee I have assembled, will greatly facilitate my research during the mentored phase as well as launch my career with the skills necessary for understanding the role of the microbiome-host- environment interactome in regulating skin barrier repair.