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：
10080752
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/10080752
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 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.

项目概要/摘要 Toll 样受体和呼吸道微生物群在肺纤维化中的相互作用特发性肺纤维化（IPF）是一种致命性疾病，目前尚无已知治愈方法、病因不明且治疗效果不佳这是一个新出现的全球健康问题，估计有 500 万人受到影响。全球每年有 17,000 人死亡。鉴定技术已经鉴定出与多种肺部疾病相关的呼吸道微生物组。使用 IPF 患者的支气管肺泡灌洗 (BAL) 液进行的临床观察支持了呼吸道微生物组，包括社区成员的变化和疾病的总体负担（生态失调）据报道，先天免疫介质包括 Toll 样受体 (TLR) 与 IPF 临床结果的关联，强调了宿主防御在 IPF 中先前被低估的作用然而，呼吸道微生物组和宿主相互作用在肺部的确切作用。人们对纤维化知之甚少，该项目的中心假设是生态失调会促进肺部进展。通过刺激 TLR 调节细胞特异性纤维化反应来抑制纤维化。采用微生物生态学、生物信息学、细胞生物学和动物模型（包括细菌自由和无菌模型）以确定生态失调在调节肺病理生理学中的作用长期目标是了解宿主-微生物群相互作用在 IPF 发病机制中的作用。并根据加深的理解为患者设计具体的治疗策略。为了实现这一目标，在无菌小鼠和常规小鼠中建立了肺纤维化动物模型将初步研究有或没有抗生素对微生物群的控制，以了解其作用菌群失调，宿主先天免疫和防御反应，并识别与菌群相关的微生物实验性肺纤维化指导后续实验性纤维化研究。缺乏与革兰氏阳性菌（Toll 样受体 2）识别相关的 TLR 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群与宿主的相互作用。在 TLR 信号传导和纤维化方面拥有丰富的经验，并且之前曾发表过该领域的职业发展文章。计划的重点是动物建模和微生物生态学生物信息学方面的进一步指导培训。该项目将通过密歇根大学医学院的部门进行内科、微生物学和免疫学系以及大学的宿主微生物组计划。这些最先进的研究将确定与纤维化相关的候选生物体，表征微生物群-宿主（TLR）相互作用可驱动纤维形成，并将凸显菌群失调所发挥的关键作用在肺纤维化的发病机制中推进我们对疾病病因学的理解，完善当前的动物模型并为这种毁灭性肺部疾病提供新的治疗策略。