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

• 批准号: 10534481
• 负责人: Kira Newman
• 金额: $ 8.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10534481
• 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; 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; Metagenomics; Methodology; Michigan; Modeling; Modification; Molecular; Mus; Observational Study; Oral; Participant; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; 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; base; 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

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.

项目摘要/摘要 炎症性肠病(IBD)在美国估计影响1.3%的成年人，并在 在全球范围内流行。宿主-微生物组的相互作用是IBD发病机制和 疾病爆发，但微生物组的非细菌成分的作用，如真核病毒和 人们对感染细菌(噬菌体)的病毒知之甚少。因此，我们建议对这一影响进行研究 微生物组的病毒成分(即病毒体)对IBD发病机制的影响。初步研究表明， 患有IBD的人的粪便是促炎的，即使与健康人的粪便相结合也是如此。 然而，推动这一效应的因素并不完全清楚。我们假设IBD中的病毒体对- 通过调节细菌微生物区系发挥炎症作用。更好地理解了 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 这项研究的目标是利用人源化的小鼠模型来表征粪便病毒转移对结肠炎的影响。 为了解决这一目标，我们建议：1.量化宿主病理、分子通路和 粪便病毒转移后的细菌群落和2.评估IBD疾病活动性的变化 在患者中伴随着粪便病毒的变化及其炎症效应。奖学金申请者 渴望成为一名独立的研究员和学术胃肠病专家，她的大部分时间都花在 开展翻译和基础科学研究。她的长期目标是了解病毒在 维持IBD微生物群的稳定性和应激反应以开发新的治疗靶点 和预防。在这项奖学金下，她将获得严格的免疫学方法论基础。 和微生物组学通过课程作业和跨学科指导。这项培训对以下工作至关重要 解决拟议的研究问题，培养作为独立调查员所需的技能，以及 实现她的长期职业目标。这一奖学金的具体目标包括：1.发展 病毒元基因组数据的分析，2.培养机械微生物组实验的高熟练程度 设计，3.在IBD动物模型的使用方面建立卓越，4.保持对 炎症性疾病的人体免疫学、微生物组学和翻译研究的趋势和发展 肠道疾病，5.通过科学写作和口头陈述继续交流研究结果，以及 6.积极寻求职业发展机会，支持向独立过渡。在……开始时 在资助期内，申请人将已完成一年的临床胃肠病学培训，并 在密歇根大学对T32进行了一年的基础科学培训。