The Relationship of Gut Microbiome and Time Restricted Feeding in Metabolism

 描述(由申请人提供)：应聘者Amir Zarrinpar博士提出了一个为期5年的职业发展计划，该计划旨在描述肠道微生物群和新陈代谢之间的关系，同时建立一个在胃肠病学领域作为内科科学家的学术生涯。肥胖及其相关的代谢性疾病困扰着美国三分之一以上的人口，是相当大的发病率和死亡率的来源。扎林帕尔博士和他的同事共同发现了限时进食(TRF)，这是一种保存正常进食/禁食周期并防止肥胖和其他与高脂肪饮食相关的代谢紊乱的范例。通过在不改变营养摄入的情况下保持自然的喂养节奏，服用TRF方案的小鼠不会变得肥胖或有代谢障碍的特征。然而，TRF的机制仍然不清楚，尽管它可能改变肠道信号和肠道微生物群。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区系表达的基因(即“转译组体”)来传递其有益的效果。这一假设将有三个具体的目标，在TRF范式的背景下调查肠道微生物群、新陈代谢和肠道基因表达之间的关系。特定目标1验证了这样的假设，即特定的TRF诱导的变化通过改变宿主-微生物组的动态平衡和管腔信号来预防肥胖。TRF将帮助确定一小部分起保护作用的候选细菌物种/基因，以及另一组在新陈代谢中起有害作用的候选细菌。特定目标2验证了这样的假设，即TRF的有益作用是由于肠道微生物群的变化而产生的。微生物群将通过使用抗生素、野生型小鼠的共享床铺或移植到无菌小鼠身上而改变。最后，《特定目标3》验证了这样的假设 肠道微生物组和转铁蛋白通过胆汁酸信号通路调节其有益作用。通过药理学操作这一信号通路，可以观察到它在介导TRF和肠道微生物群变化的有益效应中的必要性。这些特定的目标将帮助我们理解肠道微生物群在肠道内稳态、肠道基因表达和肠腔信号转导中的作用。这些实验的预期结果是，肠道微生物群是一个动态环境，微生物群落及其基因表达具有周期性变化。饮食导致的肥胖扰乱了这种动态环境，并选择了肥胖细菌。另一方面，TRF维持肠道微生物群的周期性变化，并在微生物区系中选择肥胖保护物种。微生物组的任何变化都将与肠道基因表达的变化相关联，以找到这些变化的生理后果。抗生素诱导的微生物组枯竭和无菌小鼠肠道微生物组的改变将证实微生物组的改变对于这些小鼠观察到的代谢表型是必要的。此外，胆汁酸信号通路是肠道微生物群介导其对肥胖的保护的主要途径。提出的三个具体目标将极大地促进我们对肠道微生物在新陈代谢中所起的生理作用的理解。通过更好地了解肠道微生物组与肠道内稳态、肠道基因表达和肠腔信号的关系，这些途径可以被生理学地操纵以治疗和预防肥胖及其相关的代谢性疾病。扎林帕尔博士完全有资格开展这项提案中概述的研究。作为博士论文的一部分，他已经成功地完成了相当复杂的项目。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，并进一步建立昼夜生物学、代谢调节和肠道稳态方面的专业知识。扎林帕尔博士从当地三所不同的机构招募了一支由杰出导师组成的团队。他的导师Satchidananda Panda博士在研究昼夜节律方面有经验，并使用遗传、基因组和生物化学方法识别许多受昼夜节律调节的基因。J.克雷格·文特尔研究所(JCVI)教授兼科学主任马克·亚当斯博士将提供研究肠道微生物组的专业知识。克里斯托弗·格拉斯博士在培训内科科学家方面拥有丰富的经验，他将就与职业相关的重大问题向他提供建议，并帮助他驾驭学术晋升过程。此外，全国公认的教育家和导师希拉·克罗博士将在咨询委员会任职。她将指导扎林帕尔博士发现该基因的翻译和临床应用 在他的申请中提出的研究。咨询委员会将至少每6个月举行一次会议，以确保科学计划的成功。成功完成本提案中概述的特定目标和职业发展计划将使Zarrinpar博士能够学习如何执行高质量的肠道微生物组项目，并发展成为胃肠病和新陈代谢领域的独立研究员。

 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.