Investigating the metabolic effects and de novo establishment of circadian timing differences between brain and liver

研究大脑和肝脏之间昼夜节律差异的代谢影响和从头建立

• 批准号: 10464188
• 负责人: Michael Tackenberg
• 金额: $ 6.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464188
• 关键词: Address; Affect; Bioinformatics; Biological; Brain; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Collaborations; Core Facility; Coupling; Cues; Data; Development; Diet; Disease; Doctor of Philosophy; Eating; Environment; Etiology; Exposure to; Fellowship; Functional disorder; Gene Expression Regulation; Genes; Health; Hour; Image; Individual; Intervention; Knock-out; Knowledge; Laboratories; Length; Light; Link; Liver; Maintenance; Mammals; Measures; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Modernization; Mus; Pacemakers; Pennsylvania; Periodicity; Peripheral; Phase; Physiological; Physiological Processes; Physiology; Preparation; Prevalence; Prevention; Production; Regulator Genes; Reporter; Reporter Genes; Research; Research Personnel; Research Project Grants; Running; Safety; System; Techniques; Testing; Time; Tissues; Training; Transcription Repressor; Transcriptional Regulation; Universities; Work; career development; circadian; circadian biology; circadian pacemaker; data acquisition; disorder prevention; experience; experimental study; feeding; functional genomics; glucose metabolism; improved; in vivo; lipid metabolism; metabolic rate; mouse model; obesogenic; photoperiodicity; prevent; response; skills; stem; suprachiasmatic nucleus; therapeutic target; tissue culture; transcriptome sequencing

Project Summary/Abstract Circadian disruptions are strongly associated with metabolic dysfunction, yet the mechanisms by which the circadian and metabolic systems influence one another are unclear. Elucidating the relationship between the two systems is especially important because of the prevalence of both metabolic and circadian disruptions and the safety and tractability of the circadian system as a therapeutic target. To address this need, the proposed work will determine whether changes to the relative timing of the circadian oscillators in the brain, which houses the central clock (the suprachiasmatic nucleus, or SCN) and controls feeding and metabolic rate, and liver, which controls both glucose and fat metabolism, underlie light- and diet-induced metabolic disorders. This work will test the hypothesis that relative timing of the brain and the liver is disrupted by aberrant light exposure and/or maladaptive feeding, and that this relative timing is established under typical conditions by tissue- specific period changes stemming from circadian transcriptional regulation differences. The proposed work will test these hypotheses using mouse models of clock disruption, obesogenic diets, and altered light timing to investigate the relative timing of the brain and liver and how that timing can be tuned. The resulting understanding of the origin and plasticity of the endogenous relative timing between the two tissues will provide a framework for prevention and intervention from metabolic disease with circadian etiology. The fellowship training plan developed around the research project described above will combine skills that I have developed during my Ph.D. studies with the expertise of the laboratory of my sponsor. Specifically, I will take advantage of my extensive experience with circadian biology, particularly with regards to the SCN and its influence over physiological rhythms, as well as my training in the production, maintenance, data acquisition, and analysis of organotypic tissue cultures expressing circadian clock gene reporters. I will apply these skills to the metabolic research questions described above by taking advantage of the expertise in the Lazar Lab in metabolic and liver health and functional genomic techniques. The synergistic combination of my past experience and the expertise of the Lazar Lab will thoroughly broaden and deepen my scientific and technical skillset, which will aid me in my preparation for becoming an independent investigator. The proposed experiments will be carried out at the world-class University of Pennsylvania, which will provide technical support in the form of collaboration, expertise, and core facilities as well as career development support in the form of training sessions, guidance, and networking opportunities.

项目概要/摘要 昼夜节律紊乱与代谢功能障碍密切相关，但昼夜节律紊乱的机制 昼夜节律和代谢系统相互影响尚不清楚。阐明两者之间的关系 由于代谢和昼夜节律紊乱的普遍存在，这两个系统尤其重要 昼夜节律系统作为治疗目标的安全性和易处理性。为了满足这一需求，建议 这项工作将决定大脑中昼夜节律振荡器的相对时间是否发生变化， 容纳中央时钟（视交叉上核，或 SCN）并控制摄食和代谢率，以及 肝脏负责控制葡萄糖和脂肪代谢，是光和饮食引起的代谢紊乱的基础。这 这项工作将检验以下假设：大脑和肝脏的相对时间因异常光照而受到干扰 和/或适应不良喂养，并且这种相对时间是在典型条件下由组织建立的 由于昼夜节律转录调节差异而产生的特定时期的变化。拟议的工作将 使用生物钟扰乱、肥胖饮食和改变光照时间的小鼠模型来测试这些假设 研究大脑和肝脏的相对时间以及如何调整该时间。由此产生的 了解两个组织之间内源性相对时间的起源和可塑性将提供 预防和干预具有昼夜节律病因的代谢性疾病的框架。 围绕上述研究项目制定的奖学金培训计划将结合我所掌握的技能 在我攻读博士学位期间已经发展了。借助我的资助者实验室的专业知识进行研究。具体来说，我将 利用我在昼夜节律生物学方面的丰富经验，特别是在 SCN 及其 对生理节律的影响，以及我在生产、维护、数据采集方面的训练， 以及表达生物钟基因记者的器官型组织培养物的分析。我将把这些技能应用到 利用拉扎尔实验室的专业知识解决上述代谢研究问题 代谢和肝脏健康以及功能基因组技术。我的过去的协同组合 拉扎尔实验室的经验和专业知识将彻底拓宽和深化我的科学和技术 技能，这将帮助我为成为一名独立调查员做好准备。拟议的 实验将在世界一流的宾夕法尼亚大学进行，该大学将提供技术 以协作、专业知识和核心设施以及职业发展支持的形式提供支持 形式的培训课程、指导和交流机会。