The Relationship of Gut Microbiome and Time Restricted Feeding in Metabolism

肠道微生物组与代谢中限时喂养的关系

• 批准号: 9147578
• 负责人: Amir Zarrinpar
• 金额: $ 15.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147578
• 关键词: Accounting; Adult; Advisory Committees; Affect; Agonist; Americas; Antibiotics; Asthma; Bacteria; Bacterial Genes; Beds; Bile Acids; Biochemical; Biology; Carbohydrates; Cecum; Characteristics; Circadian Rhythms; Colon Carcinoma; Development; Development Plans; Diet; Digestion; Disease; Doctor of Philosophy; Ensure; Environment; Environmental Risk Factor; Enzymes; Family; Fasting; Gastroenterology; Gene Expression; Genes; Genetic; Genomics; Germ-Free; Glass; Health; High Fat Diet; Homeostasis; Human; Inflammatory; Institutes; Institution; Intake; Learning; Mediating; Medical; Mentors; Metabolic; Metabolic Diseases; Metabolism; Morbidity - disease rate; Mus; Nutritional; Obesity; Pathway interactions; Phylogenetic Analysis; Physicians; Physiological; Play; Population; Process; Protocols documentation; Qualifying; RNA; Recruitment Activity; Regulation; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Source; Testing; Time; Training; Transgenic Organisms; Transplantation; United States; Wild Type Mouse; absorption; base; career; career development; clinical application; cost; experience; fecal transplantation; feeding; gastrointestinal function; gut microbiome; gut microbiota; intestinal homeostasis; meetings; metabolic phenotype; microbiome; mortality; mouse model; novel therapeutics; obesogenic; prevent; professor; programs; receptor; research study; transcriptome

 DESCRIPTION (provided by applicant): The candidate, Dr. Amir Zarrinpar, presents a 5-year career development plan that seeks to characterize the relationship of the gut microbiome and metabolism while establishing an academic career as a physician scientist in the field of gastroenterology. Obesity and its associated metabolic disease afflict more than one third of the population of the United States and are a source of considerable morbidity and mortality. Dr. Zarrinpar and his colleagues co-discovered time restricted feeding (TRF), a paradigm that preserves normal feeding/fasting cycles and prevents obesity and other metabolic disorders associated with a high fat diet. By maintaining the natural feeding rhythms without altering nutritional intake, mice on a TRF protocol do not become obese or have hallmarks of dysmetabolism. However, the mechanism for TRF still remains elusive, though it likely alters gut luminal signaling and the gut microbiome. Our primary hypothesis for the proposed studies is that TRF imparts its beneficial effects by altering the gut microbiome and the genes that the microflora express (i.e. "the metatranscriptome"). This hypothesis will be pursued with three specific aims that investigate the relationship between the gut microbiome, metabolism, and gut gene expression in context of the TRF paradigm. Specific aim 1 tests the hypothesis that specific TRF-induced changes protect against obesity by altering host-microbiome homeostasis and luminal signaling. TRF will help identify a small set of candidate bacterial species/genes that play a protective role and another set that play a detrimental role in metabolism. Specific aim 2 tests the hypothesis that TRF's beneficial effects result from changes in the gut microbiome. The microbiome will be changed by either using antibiotics, shared bedding in wild-type mice, or transplantation into germ-free mice. Lastly, specific aim 3 tests the hypothesis that the gut microbiome and TRF mediate their beneficial effects through bile acid signaling pathways. By pharmacologically manipulating this signaling pathway, its necessity in mediating the beneficial effects of TRF and gut microbiome changes can be observed. These specific aims will help us understand the role of gut microbiome to intestinal homeostasis, gut gene expression, and luminal signaling. The anticipated results of these experiments are that the gut microbiome is a dynamic environment with cyclical changes in microflora populations and their gene expressions. Diet induced obesity disrupts this dynamic environment and selects for obesogenic bacteria. TRF on the other hand, maintains the cyclical changes in the gut microbiome and selects for obesity-protective species in the microflora. Any changes in the microbiome will be correlated to changes in the gut gene expression to find physiological consequences of these shifts. Alteration of the gut microbiome in antibiotic induced microbiome depletion and germ-free mice would confirm that microbiome changes are necessary for the metabolic phenotype observed in these mice. Furthermore, the bile acid signaling pathway is the main way that the gut microbiome mediates its protection against obesity. The three specific aims proposed will substantially advance our understanding of the physiological role that the gut microbiome plays in metabolism. By better understanding the gut microbiome's relationship to intestinal homeostasis, gut gene expression, and luminal signaling, these pathways can then be physiologically manipulated to treat and prevent obesity and its associated metabolic diseases. Dr. Zarrinpar is well qualified to carry out the research outlined in this proposal. He has successfully completed projects of comparable complexity as part of his PhD thesis. He will further his training by acquiring expertise in performing high quality gut microbiome experiments as well as further establish expertise in circadian biology, metabolic regulation, and intestinal homeostasis. Dr. Zarrinpar has recruited a team of outstanding mentors from three different local institutions. His mentor, Dr. Satchidananda Panda, has experience in studying circadian circuitry and using genetic, genomic, and biochemical approaches to identify numerous genes that are under circadian regulation. Dr. Mark Adams, Professor and Scientific Director of J. Craig Venter Institute (JCVI) will provide expertise in studying the gut microbiome. Dr. Christopher Glass, who has extensive experience training physician scientists, will advise him on major career related issues and help navigate the academic promotion process. In addition, Dr. Sheila Crowe, a nationally recognized educator and mentor, will serve on the advisory committee. She will mentor Dr. Zarrinpar as he finds translational and clinical applications of the studies proposed in his application. The advisory committee will meet, at minimum, every 6 months to ensure a successful scientific program. Successful completion of the specific aims and career development plan outlined in this proposal will allow Dr. Zarrinpar to learn how to perform high quality gut microbiome projects and to develop into an independent investigator in the field of gastroenterology and metabolism.

 描述（由适用提供）：候选人Amir Zarrinpar博士提出了一项为期5年的职业发展计划，旨在表征肠道微生物组和代谢的关系，同时在胃肠病学领域建立了学术生涯。肥胖及其相关的代谢疾病困扰着美国人口的三分之一以上，并且是考虑发病率和死亡率的来源。 Zarrinpar博士和他的同事共同发现了限制时间（TRF），这是一种保留正常喂养/空腹周期的范式，可防止肥胖症和其他与高脂饮食相关的代谢性疾病。通过保持自然喂养节律而不改变营养摄入量，TRF方案上的小鼠不会肥胖或具有差质代谢的标志。然而，尽管它可能改变肠道信号传导和肠道微生物组，但TRF的机制仍然难以捉摸。我们对拟议研究的主要假设是，TRF通过改变肠道微生物组和微生物表达的基因（即“ metatranscriptome”）来赋予其有益效果。该假设将以三个特定的目的来提出，以研究肠道微生物组，代谢和肠道基因表达之间在TRF范式中的关系。特定的目标1检验了以下假设：特定TRF诱导的变化通过改变宿主 - 微生物组稳态和腔信号传导来预防肥胖。 TRF将有助于识别一系列候选细菌/基因，这些细菌/基因在代谢中起着受保护作用的作用，而另一组在代谢中起着有害作用。具体目标2检验了TRF的有益作用是由肠道微生物组的变化引起的假设。微生物组将通过使用抗生素，野生型小鼠共享床上用品或将其移植到无菌小鼠中来改变。最后，具体目标3检验了以下假设 肠道微生物组和TRF通过胆汁酸信号通路介导其有益作用。通过在药理操纵该信号通路时，可以观察到它在介导TRF和肠道微生物组变化的有益作用时所必需的。这些具体目标将有助于我们了解肠道微生物组在肠内稳态，肠道基因表达和腔信号传导方面的作用。这些实验的预期结果是，肠道微生物组是一个动态环境，其微生物群人群的周期性变化及其基因表达。饮食诱导的肥胖症破坏了这种动态环境，并选择肥胖细菌。另一方面，TRF保持肠道微生物组的周期性变化，并选择微生物中的肥胖保护物种。微生物组的任何变化都将与肠道基因表达的变化相关，以发现这些变化的物理后果。抗生素诱导的微生物组耗竭和无菌小鼠中肠道微生物组的改变将证实微生物组的变化对于这些小鼠中观察到的代谢表型是必需的。此外，胆汁酸信号通路是肠道微生物组介导其对肥胖症的保护的主要方式。提出的三个具体目标将大大提高我们对肠道微生物组在代谢中起的身体作用的理解。通过更好地理解肠道微生物组与肠内稳态，肠道基因表达和腔信号传导的关系，可以对这些途径进行物理操纵，以治疗和预防肥胖及其相关的代谢疾病。 Zarrinpar博士有资格进行此提案中概述的研究。作为他的博士学位论文的一部分，他成功完成了具有可比复杂性的项目。他将通过获得进行高质量肠道微生物组实验的专业知识来进一步培训，并进一步建立昼夜节律生物学，代谢调节和肠内稳态的专业知识。 Zarrinpar博士招募了来自三个当地机构的杰出导师团队。他的导师Satchidananda Panda博士在研究昼夜节律和使用遗传，基因组和生化方法的经验中识别受昼夜节律调节的许多基因。 J. Craig Venter Institute（JCVI）教授兼科学主任Mark Adams博士将在研究肠道微生物组方面提供专业知识。克里斯托弗·格拉斯（Christopher Glass）博士拥有丰富的经验培训物理科学家，他将就与职业相关的主要问题提供建议，并有助于浏览学术晋升过程。此外，全国认可的教育者和导师希拉·克劳（Sheila Crowe）博士将担任咨询委员会。她将指导Zarrinpar博士，因为他发现 在他的应用中提出的研究。咨询委员会将至少每6个月开会一次，以确保成功的科学计划。该提案中概述的特定目标和职业发展计划的成功完成将使Zarrinpar博士能够学习如何执行高质量的肠道微生物组项目，并发展成为胃肠病学和代谢领域的独立研究者。