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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：
10599330
负责人：
Elizabeth Anne Grice
金额：
$ 55.72万
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/10599330
关键词：
Adhesions Agonist Antibiotics Aryl Hydrocarbon Receptor Atopic Dermatitis Bacterial Infections Biochemical Biology Calcipotriene Cells Chronic Collaborations Cutaneous Data Defect Disease Ensure Epithelium 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 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 Skin Staphylococcus aureus Staphylococcus aureus infection Symbiosis Testing Therapeutic Tight Junctions Tissues Tryptophan Xenobiotics antimicrobial antimicrobial peptide aryl hydrocarbon receptor ligand commensal bacteria dysbiosis efficacy evaluation host microbiota improved in vivo injury recovery insight keratinocyte microbial microbial colonization microbial community microbiota mouse model multiple omics novel pathogen prevent receptor repaired safety assessment 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.

项目总结