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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

基本信息

批准号：
10689803
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
项目类别：
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/10689803
关键词：
Acne 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 Epithelium Flowers Functional disorder Genetic Transcription Germ-Free Gnotobiotic Goals Home Homeostasis Human Immune In Vitro Infection Inflammation Knock-out Ligand Binding Ligands Mass Spectrum Analysis Mediating Mentors Metagenomics Modeling Multiomic Data 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 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

项目摘要

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屏障（EPB）保护皮肤免受脱水，炎症，过早老化，老化、环境暴露和感染。表皮屏障功能障碍是特应性皮炎的重要特征，皮炎以及包括牛皮癣、痤疮和红斑痤疮在内的多种皮肤病。了根本遵循和全面了解调节内稳态屏障功能的机制对于有效预防并控制屏障异常EPB功能位于皮肤表皮，这是各种微生物群落微生物组被认为是皮肤屏障的功能单位。皮肤生态系统不断受到外部干扰的挑战，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异生素传感器，外部信号并帮助识别有益的（例如，微生物）从有害的（例如，污染物，病原体）外源性物质来调节屏障防御。最近，我证明了肠道微生物调节表皮分化和皮肤的屏障渗透性，通过激活异生素传感器，芳基碳氢化合物受体（AHR）。然而，肠道微生物调节EPB的机制， AHR下的稳态，并在存在环境损伤，如紫外线辐射是未经探讨的。中央该建议假设是通过调节AHR-上皮细胞相互作用来调节上皮细胞反应可以改变屏障渗透性。该项目通过整合转录组学，宏基因组学和代谢组学，以了解皮肤屏障修复中的宿主-微生物群相互作用。在目标1中，将从一个可以激活AHR的合成海藻群落中识别微生物信号。这些研究将从而鉴定出可用于靶向屏障疾病中的AHR的微生物配体。在目标2中，我将测试肠道微生物组在保护免受紫外线诱导的屏障损伤和使用多组学方面的贡献在AHR信号传导的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，以产生利用对环境-宿主-微生物组的理解的疗法交互.在K99阶段，我将接受代谢组学培训，以识别微生物代谢物。我会接受生物信息学和系统生物学方法的高级培训，重点是整合多个组学数据集。宾夕法尼亚大学出色的培训环境，我组建了一个优秀的咨询委员会，这将极大地促进我在指导阶段的研究同时，我也开始了我的职业生涯，掌握了理解微生物宿主的作用所必需的技能，环境相互作用组在调节皮肤屏障修复中的作用。