Microbial regulation of the keratinocyte AHR

角质形成细胞 AHR 的微生物调节

基本信息

批准号：
10467133
负责人：
Elizabeth Anne Grice
金额：
$ 57.29万
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：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467133
关键词：
Adhesions Agonist Antibiotics Aryl Hydrocarbon Receptor Atopic Dermatitis Bacterial Infections Biochemical Biology Calcipotriene Cells Chronic Collaborations Cutaneous Data Defect Disease Ensure Epithelial Flowers Functional disorder Genetic Transcription Germ-Free Goals Homeostasis Human In Vitro Infection Infection prevention Infectious Skin Diseases Inflammation Inflammatory Injury Innate Immune Response Ligands Mediating Mediator of activation protein Microbe Modeling Molecular Mus Names Ovalbumin Pathology Pathway interactions Pattern recognition receptor Permeability Pharmacodynamics Poison Predisposition Prevention Receptor Activation Receptor Signaling Regulation Relapse Research Role Safety Skin Staphylococcus aureus Staphylococcus aureus infection Symbiosis Testing Therapeutic Tight Junctions Tissues Tryptophan Xenobiotics antimicrobial antimicrobial peptide aryl hydrocarbon receptor ligand base commensal bacteria dysbiosis host microbiota improved in vivo injury recovery insight keratinocyte microbial microbial colonization microbial community microbiota mouse model multiple omics novel pathogen prevent receptor repaired skin barrier skin disorder skin lesion

项目摘要

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.

项目概要近年来，居住在健康人类皮肤中的微生物群落的复杂性已被阐明。年，以及与炎症性皮肤病（如特应性皮炎）相关的特征。然而，介导微生物与皮肤共生的分子和生化机制尚不完善明白了。我们最近发现稳态皮肤屏障功能、表皮分化和恢复免受损伤取决于小鼠体内的微生物群。这些作用是由角质形成细胞芳基介导的碳氢化合物受体（AHR）。 AHR 是外来/有毒物质的配体依赖性外源性受体众所周知，它还可以调节表皮分化、紧密连接/粘附和先天抗菌作用免疫反应。该项目的目标是识别和表征 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方面的效用。表皮屏障功能障碍是关键特应性皮炎的特征，一种常见的皮肤病，其特征是慢性和复发性、瘙痒、发炎、皮肤损伤和失调的微生物群。检验共生细菌介导 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的角质形成细胞 AHR 调节； 2) 建立微生物的药效作用 AHR 配体促进皮肤屏障功能和抗菌防御； 3) 评估微生物 AHR 配体在小鼠模型中治疗表皮屏障功能障碍和金黄色葡萄球菌感染。从这些结果中得出的结论研究将提供新颖、可实现的目标来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了解。