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）影响美国的成年人估计有1.3％，并且正在增加 全球流行。宿主 - 微生物组相互作用是IBD发病机理和 疾病耀斑，但微生物组的非细菌成分的作用，例如真核病毒和 感染细菌（噬菌体）的病毒知之甚少。因此，我们提出了对效果的研究 IBD发病机理上微生物组（即病毒群）的病毒成分的。初步研究表明 即使与健康个体的粪便结合在一起，与人类的粪便具有促炎性疾病。 但是，推动这种效果的因素尚不清楚。我们假设IBD中的病毒蛋白会施加促进 通过调节细菌微生物群的炎症作用。改善了对角色的理解 IBD中的病毒将为微生物疗法的发展和临床结果预测提供信息。这 研究的目标是使用人源化小鼠模型来表征粪便病毒蛋白转移对结肠炎的影响。 为了解决这个目标，我们建议：1。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。 在患者中，粪便病毒及其炎症作用的变化。奖学金申请人 渴望成为独立的研究者和学术胃肠病学家，大部分时间都花在 进行翻译和基础科学研究。她的长期目标是了解病毒在 维持微生物组的稳定性和对IBD压力的反应，以开发出新的治疗目标 和预防。根据这项奖学金，她将获得严格的免疫方法基础 以及通过课程和跨学科心理的微生物“ OMICS”。这项培训对于 解决拟议的研究问题，发展作为独立研究者必要的技能，以及 实现她的长期职业目标。该奖学金的具体目标包括：1。发展专业知识 分析病毒宏基因组数据，2。基于机械菌群的实验培养高熟练程度 设计，3。在IBD使用动物模型方面建立卓越的卓越，4。保持积极的了解 人类免疫学，微生物“ OMICS和转化研究的趋势和发展” 肠病，5。通过科学写作和口头演示继续进行调查结果，以及 6。积极寻求职业发展机会，以支持过渡到独立性。在开始时 资金期，申请人将完成一年的临床胃肠病学培训和 密歇根大学的T32基础科学培训一年。