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Toll-like Receptors and Respiratory Microbiota Interactions in Idiopathic Pulmonary

特发性肺病中 Toll 样受体与呼吸道微生物群的相互作用

基本信息

批准号：
10322442
负责人：
David Noel O'Dwyer
金额：
$ 24.9万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322442
关键词：
Affect Animal Disease Models Animal Experimentation Animal Model Animals Antibiotics Area Bacteria Bioinformatics Biological Response Modifiers Bleomycin Bronchoalveolar Lavage Fluid Cells Cellular biology Cessation of life Clinical Communities Culture-independent methods Data Development Development Plans Disease Disease Progression Ecology Etiology Fibrosis Firmicutes Functional disorder Future Gene Expression Germ-Free Gnotobiotic Goals Gram-Negative Bacteria Heterogeneity Host Defense Human Immune Immunology Inflammation Inflammatory Innate Immune Response Internal Medicine Interstitial Lung Diseases Knowledge Laboratories Lead Ligands Lung Lung diseases Measures Mentors Michigan Microbe Microbiology Modeling Mus National Heart, Lung, and Blood Institute Organ Organism Outcome Pathogenesis Patients Persons Phase Physicians Play Prevalence Progressive Disease Proteobacteria Publishing Pulmonary Fibrosis Pulmonology Receptor Activation Receptor Cell Receptor Signaling Recommendation Reporting Research Role Scientist Series Strategic Planning TLR2 gene TLR4 gene Techniques Therapeutic Toll-like receptors Training United States Universities Wild Type Mouse base career development defense response design dysbiosis experience experimental study fibrogenesis global health host microbiome host microbiota idiopathic pulmonary fibrosis improved indium-bleomycin lung microbiota medical schools member microbial microbiome microbiota mortality mouse toll-like receptor 2 novel novel therapeutic intervention respiratory respiratory microbiome respiratory microbiota response skills wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT Toll-like receptor and respiratory microbiota interactions in pulmonary fibrosis Idiopathic pulmonary fibrosis (IPF) is a lethal disease with no known cure, unknown etiology and poorly understood pathogenesis. It is an emerging global health issue with an estimated 5 million people affected worldwide and 17,000 deaths in the United States annually. The advent of culture-independent microbial identification techniques has identified a respiratory microbiome associated with several lung diseases. Novel clinical observations using bronchoalveolar lavage (BAL) fluid from IPF patients support a role for the respiratory microbiome, both changes in community members and overall burden (dysbiosis) in disease progression and mortality. Innate immune mediators including Toll-like receptors (TLR) have reported associations with clinical outcomes in IPF, highlighting the previously underappreciated role of host defense in IPF pathogenesis. However, the precise role of the respiratory microbiome and host interaction in pulmonary fibrosis is poorly understood. The central hypothesis of this project is that dysbiosis promotes progressive lung fibrosis through stimulation of TLRs to modulate cell-specific fibrotic responses. The specific objective is to employ techniques from microbial ecology, bioinformatics, cell biology and animal modeling (including germ free and gnotobiotic models) to determine the role of dysbiosis in regulating lung pathophysiology in pulmonary fibrosis. The long term goal is to understand the role of host-microbiota interactions in the pathogenesis of IPF and design specific therapeutic strategies for patients based on an improved understanding. In order to achieve this objective, established animal models of pulmonary fibrosis in germ free and conventional mice with or without antibiotic manipulation of the microbiota will be studied initially to understand the role of dysbiosis, the host innate immune and defense response and to identify microbes associated with experimental pulmonary fibrosis to guide gnotobiotic studies. Subsequent studies of experimental fibrosis in animal models deficient in TLRs associated with the recognition of Gram positive (Toll-like receptor 2) and Gram negative bacteria (Toll-like receptor 4) will further define microbiota-host interactions. Dr. O’Dwyer has experience in TLR signaling and fibrosis and has previously published in this area. His career development plan is focused on further mentored training in animal modeling and the bioinformatics of microbial ecology. This project will be undertaken within the University of Michigan’s Medical School through the Department of Internal Medicine, Department of Microbiology and Immunology and the University’s Host Microbiome Initiative. These state-of-the-art studies will identify candidate organisms associated with fibrosis, characterize microbiota-host (TLR) interactions that drive fibrogenesis and will highlight the crucial role that dysbiosis plays in the pathogenesis of lung fibrosis to advance our understanding of disease etiology, refine current animal models and inform new therapeutic strategies for this devastating lung disorder.

项目摘要/摘要肺纤维化中Toll样受体与呼吸道微生物区系的相互作用特发性肺纤维化(IPF)是一种致命的疾病，没有已知的治愈方法，病因不明，了解发病机制。这是一个新兴的全球健康问题，估计有500万人受到影响全球每年有17,000人死亡。不依赖培养的微生物的出现鉴定技术已经鉴定出一种与几种肺部疾病有关的呼吸道微生物群。小说使用IPF患者的支气管肺泡灌洗液(BAL)的临床观察支持呼吸道微生物组，既包括社区成员的变化，也包括疾病的总体负担(生物失调) 进展和死亡率。包括Toll样受体(TLR)在内的先天免疫介质已有报道与IPF临床结局的相关性，强调了先前被低估的宿主防御在IPF中的作用 IPF发病机制。然而，呼吸道微生物群和宿主相互作用在肺炎性疾病中的确切作用人们对纤维化知之甚少。该项目的中心假设是，生物失调促进进展性肺。通过刺激TLRs来调节细胞特异性的纤维化反应。具体目标是使用微生物生态学、生物信息学、细胞生物学和动物模型(包括细菌)的技术 FREE和GNOTIONIC模型)以确定失调在调节肺组织病理生理学中的作用纤维化症。长期目标是了解宿主-微生物区系相互作用在IPF发病机制中的作用。并在加深了解的基础上为患者设计具体的治疗策略。为了为了实现这一目标，建立了无菌和常规小鼠肺纤维化的动物模型无论有没有抗生素对微生物区系的操纵都将进行初步研究，以了解生物失调，宿主的先天免疫和防御反应，并识别与之相关的微生物实验性肺纤维化指导生药学研究。实验性肝纤维化的后续研究与革兰氏阳性(Toll样受体2)和Toll样受体识别相关的TLRs缺乏的动物模型革兰氏阴性细菌(Toll样受体4)将进一步定义微生物区系与宿主的相互作用。奥德怀尔医生已经在TLR信号转导和纤维化方面的经验，并以前在这一领域发表过。他的职业发展该计划的重点是动物建模和微生物生态学的生物信息学方面的进一步指导培训。该项目将在密歇根大学医学院内通过内科、微生物学和免疫学系以及该大学的宿主微生物组倡议。这些最先进的研究将确定与纤维化相关的候选微生物，表征微生物区系-宿主(TLR)的相互作用推动了纤维化的发生，并将突出生物失调所起的关键作用在肺纤维化的发病机制上提高我们对疾病病因的认识，提炼目前的动物为这种毁灭性的肺部疾病建立模型并提供新的治疗策略。