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

解码皮肤屏障界面处的微生物-芳基烃受体相互作用

• 批准号: 10507321
• 负责人: AAYUSHI UBEROI
• 金额: $ 9.06万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507321
• 关键词: Adhesions; Advisory Committees; Air Pollutants; Allergens; Aryl Hydrocarbon Receptor; Atopic Dermatitis; Attenuated; Bioinformatics; Communities; Complex; Coupled; Data Set; Dehydration; Disease; Ecology; Ecosystem; Environment; Environmental Exposure; Epidermis; Epithelial; Flowers; Functional disorder; Genetic Transcription; Germ-Free; Gnotobiotic; Goals; Home; Homeostasis; Human; Hypersensitivity skin testing; Immune; In Vitro; Infection; Inflammation; Knock-out; Lead; Ligand Binding; Ligands; Mass Spectrum Analysis; Mediating; Mentors; Metagenomics; Modeling; Mus; Names; Pathway interactions; Patients; Pennsylvania; Permeability; Phase; Precision therapeutics; Premature aging syndrome; Probiotics; Psoriasis; Receptor Signaling; Regulation; Research; Resources; Role; Rosacea; Signal Transduction; Skin; Skin repair; System; Systems Biology; Testing; Therapeutic; Tight Junctions; Training; Tryptophan; Tryptophan Metabolism Pathway; UV induced; Ultraviolet Rays; Universities; Xenobiotics; aryl hydrocarbon receptor ligand; base; career; cell type; commensal microbes; design; efficacy testing; epithelial repair; high throughput screening; host microbiome; host microbiota; improved; inhibitor; member; metabolomics; metagenomic sequencing; microbial; microbial community; microbiome; microbiota; mouse model; multiple omics; novel therapeutics; pathogen; pollutant; prevent; repaired; response; sensor; skills; skin barrier; skin disorder; skin microbiome; targeted treatment; therapeutic evaluation; tool; transcription factor; transcriptome sequencing; transcriptomics

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.

项目概要 有效的表皮渗透屏障（EPB）可保护皮肤免受脱水、炎症、早产的影响 衰老、环境暴露和感染是特应性皮肤病的一个重要特征。 皮炎，以及许多皮肤病，包括牛皮癣、痤疮和红斑痤疮。 全面了解调节稳态屏障功能的机制对于有效预防 EPB 功能位于皮肤表皮，这是多种细胞的所在地。 微生物群落被认为是皮肤屏障的功能单位。 生态系统不断受到外部暴露的挑战，包括紫外线辐射（UVR）、空气 污染物和过敏原对于屏障防御和体内平衡至关重要的是能够识别的外源传感器。 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、 最近，我证明了共生微生物可以调节屏障防御。 通过激活异生传感器芳基来调节表皮分化和皮肤屏障通透性 然而，共生微生物通过碳氢化合物受体（AHR）调节 EPB 的机制。 稳态下的 AHR 以及存在 UVR 等环境侵害的情况尚未被探索。 该提议的假设是通过调节 AHR 共生相互作用来调整上皮反应 该项目通过整合转录组学来利用“多组学”方法， 在目标 1 中，我通过宏基因组学和代谢组学来了解皮肤屏障修复中宿主-微生物群的相互作用。 将识别来自合成共生群落的微生物信号，这些信号可以激活 AHR。 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，我将进行测试。 共生微生物组在防止紫外线引起的屏障损伤方面的贡献并使用多组学 这些研究在 AHR 信号传导背景下表征微生物组-宿主-UV 相互作用组的方法。 将提供一个框架来产生利用对环境-宿主-微生物组的理解的疗法 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。 接受生物信息学和系统生物学方法的高级培训，重点关注整合多种方法 宾夕法尼亚大学出色的培训环境以及 我组建的优秀顾问委员会将极大地促进我在指导阶段的研究 以及以了解微生物组-宿主-的作用所需的技能开始我的职业生涯 环境相互作用组调节皮肤屏障修复。