Diurnal Oscillations in Gut Microbes and Host Immunity in Health and Obesity

肠道微生物的昼夜振荡以及健康和肥胖中的宿主免疫

• 批准号: 10322790
• 负责人: Vanessa Anne Leone
• 金额: $ 12.57万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-16 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322790
• 关键词: Address; Area; Automobile Driving; Award; Benchmarking; Bioinformatics; Biological; Biology; C-Type Lectins; Carbohydrates; Chicago; Chronobiology; Circadian Rhythms; Cues; Data; Development; Diet; Disease; Distal; Diurnal Rhythm; Educational workshop; Environment; Epidemic; Evaluation; Exhibits; Fatty acid glycerol esters; Feedback; Gene Expression Profile; Generations; Germ-Free; Goals; Grant; Health; Health Care Costs; High Fat Diet; Hour; Housing; Immune; Immunity; In Vitro; Integration Host Factors; Intestines; Investments; Jet Lag Syndrome; Knock-out; Knowledge; Laboratories; Lead; Light; Maintenance; Manuscripts; Mentored Research Scientist Development Award; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Microbe; Microbiology; Molecular; Mucous Membrane; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Immunity; Natural regeneration; Nature; Obesity; Outcome; Output; Pattern; Peptide Synthesis; Play; Preparation; Principal Investigator; Publications; Research; Research Design; Research Methodology; Research Personnel; Ribosomal RNA; Role; Shift-Work Sleep Disorder; Shotguns; Signal Transduction; Sleep Apnea Syndromes; Sleep Wake Cycle; Small Intestines; Structure; Techniques; Testing; Time; Time Series Analysis; TimeLine; Training; Training Programs; Transgenic Organisms; Universities; Work; antimicrobial; antimicrobial peptide; base; career; career development; circadian; design; diet-induced obesity; dysbiosis; feeding; gut microbes; gut microbiota; host-microbe interactions; in vivo; innate immune function; insight; islet; knowledge base; member; metabolome; metabolomics; metagenome; microbial; microbial community; microorganism interaction; obesity development; prevent; response; saturated fat; skill acquisition; tool; western diet

PROJECT SUMMARY I am applying for a Mentored Research Scientist Development Award from NIDDK to facilitate my transition to an independent investigator studying host-microbe interactions and metabolic diseases. I am an experimental biologist with extensive training examining host-microbe interactions in health and disease. My recent publication under the mentorship of Dr. Eugene B. Chang identified that gut microbes exhibit diurnal patterns that are tightly aligned with host circadian rhythm. Diet-induced microbial dysbiosis disrupts this interaction, leading to development of obesity. My proposal will focus on filling gaps in knowledge to define the underlying mechanisms that drive daily microbial oscillations. I will examine the interplay between innate immune functions and diurnal patterns of intestinal microbes located within the distal small intestine. My long- term goal is to gain insights into the bi-directional relationship between host and microbe that leads to the resetting of the localized intestinal clock. I have designed the career development benchmarks of this K01 award to expand my knowledge base and gain expertise in the areas of molecular circadian biology, microbiology, and innate immune function. I have gathered a mentorship team to oversee my proposed work, which will be lead by Dr. Eugene B. Chang. I will be co-mentored by Drs. Brian J. Prendergast (UChicago), Eve Van Cauter (UChicago), and Mitchell L. Sogin (Marine Biological Laboratory). The mentorship team has participated in designing the career training program and approved the proposed research timeline, coursework, skill development workshops, and manuscript/grant submission timeline. They will be involved throughout the award to provide guidance and oversight for research design and methods, troubleshooting, scientific direction and evaluation, as well as preparation of manuscripts, grants, and presentations. I will receive additional support via my department and division chairs as well as a group of consultants, including Drs. Jennifer Evans (Marquette University – molecular circadian biology), Aaron Dinner (University of Chicago – statistical approaches for circadian time series analysis), A. Murat Eren (University of Chicago – Microbial community analysis), and Dean P. Jones (Emory University – metabolomics). The research environment at the University of Chicago is ideal to accomplish my proposed research aims and provides all necessary tools to successfully complete my goals. I will examine the underlying mechanisms that drive daily oscillations in gut microbes, specifically the interplay between innate immune functions and distal small intestinal microbes. I observed that oscillations of gut microbes are synchronized with host diurnal expression patterns of genes involved in antimicrobial peptide synthesis, specifically regenerating islet-derived 3 gamma (Reg3γ). How diurnal patterns in Reg3γ expression aid in maintenance of normal gut microbial oscillations and what the implications are for host metabolic health remain unexplored. The long-term goal is to determine how oscillations of gut microbes influence diurnal dynamics of intestinal host factors that aid in maintenance of a host-microbe symbiotic relationship. This knowledge could lead to development of new strategies to prevent and treat diet-induced obesity.

项目概要 我正在申请 NIDDK 指导研究科学家发展奖，以促进我的过渡 一位研究宿主-微生物相互作用和代谢疾病的独立研究者。我是一个 接受过广泛培训的实验生物学家，研究宿主与微生物在健康和疾病方面的相互作用。我的 最近在 Eugene B. Chang 博士的指导下发表的论文指出，肠道微生物表现出昼夜节律 与宿主昼夜节律紧密一致的模式。饮食引起的微生物失调破坏了这一点 相互作用，导致肥胖的发生。我的建议将侧重于填补知识空白，以定义 驱动日常微生物振荡的潜在机制。我将研究先天之间的相互作用 位于远端小肠内的肠道微生物的免疫功能和昼夜模式。我的长- 术语目标是深入了解宿主和微生物之间的双向关系，从而导致 重置局部肠道时钟。 我设计了这个K01奖的职业发展基准，以扩展我的知识库和 获得分子昼夜节律生物学、微生物学和先天免疫功能领域的专业知识。我有 组建了一个导师团队来监督我提议的工作，该团队将由 Eugene B. Chang 博士领导。我会 由博士共同指导。 Brian J. Prendergast（芝加哥大学）、Eve Van Cauter（芝加哥大学）和 Mitchell L. Sogin （海洋生物实验室）。导师团队参与设计职业培训方案 并批准了拟议的研究时间表、课程作业、技能发展研讨会和手稿/拨款 提交时间表。他们将参与整个颁奖过程，为项目提供指导和监督 研究设计和方法、故障排除、科学方向和评估以及准备 手稿、赠款和演示文稿。我将通过我的部门和分部主席获得额外支持 以及一组顾问，包括博士。 Jennifer Evans（马凯特大学 – 分子昼夜节律） 生物学），Aarondinner（芝加哥大学 - 昼夜节律时间序列分析的统计方法），A. Murat Eren（芝加哥大学 - 微生物群落分析）和 Dean P. Jones（埃默里大学 - 代谢组学）。芝加哥大学的研究环境非常适合完成我的提议 研究旨在并提供所有必要的工具来成功完成我的目标。 我将研究驱动肠道微生物日常振荡的潜在机制，特别是 先天免疫功能和远端小肠微生物之间的相互作用。我观察到振荡 肠道微生物与宿主抗菌肽相关基因的昼夜表达模式同步 合成，特别是再生胰岛衍生的 3 γ (Reg3γ)。 Reg3γ 表达的昼夜模式如何 有助于维持正常的肠道微生物振荡及其对宿主代谢健康的影响 仍未被探索。长期目标是确定肠道微生物的振荡如何影响昼夜节律。 有助于维持宿主-微生物共生关系的肠道宿主因素的动态。这 知识可以导致制定预防和治疗饮食引起的肥胖的新策略。