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.

项目总结/摘要 昼夜节律紊乱与代谢功能障碍密切相关，然而， 昼夜节律和代谢系统的相互影响尚不清楚。阐明了 由于代谢和昼夜节律紊乱的普遍存在， 昼夜节律系统作为治疗靶点的安全性和易处理性。为了满足这一需求，建议 这项工作将确定是否改变了大脑中昼夜节律振荡器的相对时间， 容纳中央时钟（视交叉上核，或SCN）并控制进食和代谢率， 控制葡萄糖和脂肪代谢的肝脏是光和饮食诱导的代谢紊乱的基础。这 这项工作将检验大脑和肝脏的相对时间被异常的光照破坏的假设 和/或适应不良的喂养，并且这种相对定时是在典型条件下由组织- 特定时期的变化源于昼夜转录调控差异。拟议的工作将 使用生物钟中断、致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时间。所得 了解这两种组织之间内源性相对定时的起源和可塑性， 预防和干预具有昼夜节律病因学的代谢性疾病的框架。 围绕上述研究项目制定的研究金培训计划将联合收割机的技能，我 在我读博士期间发展起来的。研究与我的赞助商的实验室的专业知识。具体来说，我会 利用我在昼夜节律生物学方面的丰富经验，特别是关于SCN及其 对生理节律的影响，以及我在生产，维护，数据采集， 和分析表达生物钟基因报告基因的器官型组织培养物。我将把这些技能应用到 通过利用Lazar实验室的专业知识， 代谢和肝脏健康以及功能基因组技术。我的过去 经验和专业知识的拉扎尔实验室将彻底拓宽和深化我的科学和技术 技能，这将有助于我准备成为一名独立调查员。拟议 实验将在世界一流的宾夕法尼亚大学进行，该大学将提供技术支持。 以合作、专业知识和核心设施的形式提供支持，以及在 培训课程、指导和网络机会的形式。