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.

项目摘要 有效的表皮渗透性屏障（EPB）可保护皮肤免于脱水，注射，过早 衰老，环境暴露和感染。表皮屏障功能障碍是特征的重要特征 皮炎以及包括牛皮癣，痤疮和酒渣鼻在内的许多皮肤病。一个基本和 对调节稳态屏障功能的机制的整体理解对于有效防止 并管理障碍异常。 EPB功能位于皮肤表皮中，这是潜水员的家园 微生物社区。微生物组被认为是皮肤屏障的功能单元。皮肤 生态系统不断受到包括紫外线辐射（UVR），空气在内的外部展示体的挑战 污染物和过敏原。对屏障防御和体内平衡至关重要的是识别的异生物传感器 外部信号并有助于确定有害的有益（例如，共生微生物）（例如污染物，， 病原体）异生物学以调节屏障防御。最近，我证明了共生微生物 通过激活异种生物传感器（芳基）调节皮肤表皮分化和屏障渗透性 碳氢化合物受体（AHR）。但是，共同微生物通过 在体内稳态下的AHR，在存在环境侮辱的情况下，例如UVR是出乎意料的。中央 该提议的假设是通过调节AHR - 符合性相互作用来调整上皮反应 可以改变屏障渗透性。该项目通过整合转录组学来利用“多摩斯”方法， 宏基因组学和代谢组学了解皮肤屏障修复中的宿主 - 微生物群相互作用。在AIM 1中，我 将从合成的共生社区中识别可激活AHR的微生物信号。这些研究会 导致鉴定可用于靶向屏障疾病的AHR的微生物配体。在AIM 2中，我将测试 共生微生物组在防止紫外线诱导的屏障损伤和使用多组合方面的贡献 在AHR信号传导的背景下，表征微生物组 - 霍斯特-UV相互作用组的方法。这些研究 将提供一个框架，以生成利用对环境宿主 - 麦克罗姆的理解的疗法 互动。在K99阶段，我将接受代谢组学培训，以鉴定微生物代谢物。我会 接受生物信息学和系统生物学方法的高级培训，这些方法专注于整合多个 OMICS数据集。宾夕法尼亚大学出色的培训环境以及 我组装的优秀咨询委员会将在修订阶段大大支持我的研究 以及我的职业生涯以及了解微生物组主持人的作用所必需的技能 - 环境在控制皮肤屏障修复方面相互作用。