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Bacterial, Viral, and Host Interactions in the Pathogenesis of Inflammatory Bowel Disease

炎症性肠病发病机制中的细菌、病毒和宿主相互作用

基本信息

批准号：
10657414
负责人：
Kira Newman
金额：
$ 8.37万
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：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10657414
关键词：
Address Adult Affect Animal Model Automobile Driving Bacteria Bacterial Genome Bacteriophages Basic Science Biological Models Chronic Clinical Colitis Communication Communities Complex Cytolysis Data Development Disease Enterobacteriaceae Experimental Designs Feces Fellowship Filtration Flare Fostering Foundations Funding Gastroenterologist Gastroenterology Germ-Free Goals Human Human Microbiome Immunologics Immunology Individual Inflammation Inflammatory Inflammatory Bowel Diseases Interferon Type II K-Series Research Career Programs Knowledge Literature Maintenance Medical Mentorship Metabolic Metabolic Pathway Metabolism Metagenomics Methodology Michigan Modeling Modification Molecular Mus Observational Study Oral Participant Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Physiological Predisposition Prevalence Prevention Research Research Personnel Role Severities Shapes Stress T-Cell Activation Therapeutic Time Training Translational Research United States Universities Viral Virus Work Writing bacterial community bacterial fitness bacteriome burden of illness career career development dysbiosis fecal microbiome fecal transplantation gut bacteria gut inflammation gut microbiome gut microbiota host microbiome humanized mouse improved metabolome microbial microbiome microbiome alteration microbiome components microbiota mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics pathobiont predict clinical outcome prediction algorithm response skills trend virome

项目摘要

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD) affects an estimated 1.3% of adults in the United States and is increasing in prevalence globally. Host-microbiome interactions are an important contributor to IBD pathogenesis and disease flares, but the role of non-bacterial components of the microbiome, such as eukaryotic viruses and viruses that infect bacteria (bacteriophages), are less understood. Therefore, we propose a study of the effect of the viral component of the microbiome (i.e. virome) on IBD pathogenesis. Preliminary studies suggest that stool from humans with IBD is pro-inflammatory, even when combined with stool from healthy individuals. However the factors driving this effect are not fully known. We hypothesize that the virome in IBD exerts a pro- inflammatory effect through modulation of the bacterial microbiota. Improved understanding of the role of viruses in IBD will inform the development of microbial therapeutics and prediction of clinical outcomes. This study’s goal is to characterize the effects of fecal virome transfer on colitis using a humanized mouse model. To address this goal, we propose: 1. To quantify the changes in host pathology, molecular pathways, and bacterial communities following fecal viral transfer and 2. To evaluate whether changes in IBD disease activity in patients is accompanied by changes in fecal viruses and their inflammatory effects. The fellowship applicant aspires to become an independent investigator and academic gastroenterologist, with most of her time spent conducting translational and basic science research. Her long-term goal is to understand the role of viruses in the maintenance of microbiome stability and response to stress in IBD to develop novel targets for treatment and prevention. Under this fellowship, she will acquire a rigorous methodological foundation in immunology and microbial ‘omics through coursework and interdisciplinary mentorship. This training will be essential to address the proposed research question, develop the skills necessary as an independent investigator, and achieve her long-term career goals. Specific goals for this fellowship include: 1. Developing expertise in the analysis of viral metagenomic data, 2. Fostering high proficiency in mechanistic microbiota-based experimental design, 3. Building excellence in the use of animal models for IBD, 4. Maintaining an active understanding of trends and developments in human immunology, microbial ‘omics, and translational research in inflammatory bowel disease, 5. Continued communication of findings through scientific writing and oral presentations, and 6. Actively pursuing career development opportunities to support transitioning to independence. At the start of the funding period, the applicant will have already completed one year of clinical gastroenterology training and one year of basic science training on a T32 at the University of Michigan.

项目总结/摘要在美国，炎症性肠病（IBD）影响约1.3%的成年人，全球流行。宿主-微生物组相互作用是IBD发病机制的重要贡献者，疾病爆发，但微生物组的非细菌成分的作用，如真核病毒和感染细菌的病毒（噬菌体），了解较少。因此，我们建议研究微生物组的病毒组分（即病毒组）对IBD发病机制的影响。初步研究表明，患有IBD的人的粪便是促炎性的，甚至当与健康个体的粪便结合时也是如此。然而，驱动这种效应的因素并不完全清楚。我们假设IBD中的病毒组发挥了促进作用，通过细菌微生物群的调节来调节炎症作用。更好地了解 IBD中的病毒将为微生物疗法的发展和临床结果的预测提供信息。这这项研究的目的是使用人源化小鼠模型来描述粪便病毒组转移对结肠炎的影响。为了实现这一目标，我们建议：1。为了量化宿主病理学、分子途径和粪便病毒转移后的细菌群落和2.评价IBD疾病活动性的变化是否在患者中，伴随着粪便病毒的变化及其炎症作用。研究金申请人她渴望成为一名独立的研究者和学术胃肠病学家，她的大部分时间都花在开展转化和基础科学研究。她的长期目标是了解病毒在维持IBD中微生物组的稳定性和对应激的反应，以开发新的治疗靶点和预防在此奖学金下，她将获得免疫学的严格方法学基础和微生物组学。这项培训将是必不可少的，解决拟议的研究问题，发展作为独立调查员所需的技能，实现长期职业目标。该奖学金的具体目标包括：1。发展下列领域的专门知识：病毒宏基因组数据的分析，2.培养高水平的机械微生物实验能力设计，3.建立卓越的IBD动物模型，4。积极理解人类免疫学、微生物组学和炎症转化研究的趋势和发展肠道疾病，5。通过科学写作和口头报告继续交流研究结果， 6.积极寻求职业发展机会，以支持向独立过渡。开始时在资助期内，申请人须已完成一年的临床肠胃病学训练，在密歇根大学的T32上接受了一年的基础科学训练。