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Role of Microbiome Sodium Butyrate in regulation of ILC2 dependent airway hyperreactivity

微生物组丁酸钠在调节 ILC2 依赖性气道高反应性中的作用

基本信息

批准号：
9352668
负责人：
OMID AKBARI
金额：
$ 24.75万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-18 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352668
关键词：
Address Adoptive Transfer Adverse effects Affect Aftercare Allergens Allergic Allergic Disease Alternaria Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibiotics Asthma Bacteria Butyrates Cell physiology Cells Clinical Clinical Trials Colon Communication Data Developed Countries Developing Countries Development Diet Dietary Fiber Disease Distal Effector Cell Eosinophilia Epithelial Cells Extrinsic asthma FFAR2 gene FFAR3 gene Fermentation Gastrointestinal tract structure General Population Goals Helminths Human I Kappa B-Alpha Immune response Immunity Immunosuppression Inbred BALB C Mice Incidence Inflammation Inflammatory Interleukin-13 Interleukin-5 Interleukins Intestines Life Liquid substance Lung Lung Inflammation Lung diseases Lymphoid Cell Mammals Measures Methods Microbe Molecular Molecular Profiling Mucous body substance Mus Natural Immunity Nature Organ Pathogenesis Pathway interactions Patients Peptides Phenotype Physiological Play Population Pre-Clinical Model Prevalence Production Property Propionates Public Health Pulmonary Inflammation Regulation Reporting Research Project Grants Research Proposals Respiratory System Respiratory physiology Role Signal Transduction Sodium Butyrate Source Testing Therapeutic Therapeutic Intervention Time Tissues Translating Translational Research Volatile Fatty Acids Wild Type Mouse adaptive immunity airway hyperresponsiveness allergic airway inflammation antimicrobial base cell type cytokine eosinophilic inflammation gut microbiome gut microbiota humanized mouse implantation improved in vivo inflammatory lung disease inflammatory marker microbial microbiome microbiota molecular marker mouse model novel novel therapeutic intervention prevent receptor respiratory response therapeutic target transcription factor transcriptome translational approach

项目摘要

PROJECT SUMMARY Group 2 innate lymphoid cells (ILC2s) constitute a recently identified cell population that produces type 2 cytokines such as IL-5 and IL-13 in response to a growing number of environmental signals and epithelial cell-derived cytokines. Initially described as a key source of IL-13 in anti-helminth innate immunity, studies now show increased ILC2 activity in asthma and many widespread allergic diseases. In murine models of asthma, ILC2s are sufficient to provoke eosinophilic inflammation accompanied by airway hyperreactivity (AHR) independent of adaptive immunity. Based on these findings, identifying agents capable of modulating ILC2 function is an important step towards advancing treatment of asthma. This project is motivated by our recent finding that sodium butyrate, a short-chain fatty acid (SCFA) naturally present in our body’s tissues and fluids, significantly suppresses the production of type 2 cytokines by ILC2s and relieves ILC2-dependent AHR. We additionally found that pulmonary ILC2s highly express a receptor for sodium butyrate, GPR109a and do not express GPR41 or GPR43. Further transcriptome analyses revealed that GATA-3, a key transcription factor in ILC2 development and function, was significantly down-regulated after treatment with sodium butyrate. Given that intestinal bacteria are the predominant source of butyrate in mammals, we now propose to characterize the mechanisms by which microbial-derived sodium butyrate potentially modulates ILC2 effector function in distal tissues and reduces ILC2-dependent AHR. The overall goal of this research project is to discover a comprehensive set of molecular signatures and markers that can be used as therapeutic targets to treat allergic disease and asthma. In order to achieve this objective, we will first fully characterize the phenotype, function, and mechanisms of action of sodium butyrate in animal models of AHR. Next, utilizing a recently described ILC2 humanized mice (Maazi et al, Immunity 2015, Galle et al, Nature Communications 2016), we intend to assess the capacity for therapeutic intervention in the presence of absence of GPR109a receptor. Finally, we will aim to prevent development of ILC2 dependent AHR via altering microbiome of mice with high butyrate producing strains of bacteria and compare the results to the recipients of microbiome without capacity to produce butyrate. This translational research proposal will provide critical clues that enable us to develop therapeutic approaches for the treatment of patients with allergic disease and asthma.

项目总结