Unraveling the molecular connections that link circadian rhythms and lipid metabolism

揭示昼夜节律和脂质代谢之间的分子联系

• 批准号: 10559559
• 负责人: XUEMIN WANG
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF MISSOURI-ST. LOUIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559559
• 关键词: Address; Affect; Amino Acids; Arabidopsis; Binding; Biological Assay; Biosensor; Cell Nucleus; Cell Proliferation; Cell model; Cells; Circadian Dysregulation; Circadian Rhythms; Darkness; Data; Disease; Environment; Enzymes; Eukaryota; Feedback; Fostering; Functional disorder; Future; Gene Expression; Genes; Genetic Transcription; Glycerolipid Metabolism Pathway; Goals; Health; Homeostasis; Human; Hypocotyl; Knowledge; Lead; Light; Link; Lipid Binding; Lipids; Liposomes; Location; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mission; Modeling; Molecular; Monitor; Mouse-ear Cress; Mutagenesis; Mutation; Outcome; Output; Pathologic Processes; Pathway interactions; Phosphatidic Acid; Physiological; Physiology; Plants; Process; Production; Regulation; Regulator Genes; Research; Role; Signal Transduction; Specificity; Surface Plasmon Resonance; Testing; United States National Institutes of Health; Work; biological adaptation to stress; chromatin immunoprecipitation; circadian; circadian pacemaker; circadian regulation; data mining; day length; experimental study; genome editing; improved; in vivo; innovation; insight; lipid mediator; lipid metabolism; lipidomics; model organism; mutant; novel; response; screening; transcription factor

PROJECT SUMMARY Misalignments and disruption of the circadian clock lead to metabolic and physiological dysfunctions. The clock regulates metabolism whereas metabolic activities feedback to influence circadian rhythms, and this interplay between the clock and metabolism coordinates physiology. However, one major knowledge gap is the limited understanding of the mechanism by which metabolism affects clock function. The goal of the proposed research is to elucidate the molecular mechanism by which the circadian clock and lipid metabolism are interconnected through the interaction and reciprocal regulation between lipid mediators and major clock regulators using the model organism Arabidopsis thaliana. The feasibility of the proposed research is supported by recent findings that the central glycerolipid metabolic intermediate, phosphatidic acid (PA), directly binds to the clock transcription factor LHY (LATE ELONGATED HYPOCOTYL), manipulations of PA-metabolizing activities alter clock outputs, and disruptions of the clock perturb lipid accumulation in Arabidopsis. The hypothesis is that the PA-LHY interaction functions as a cellular conduit to integrate the circadian clock with lipid metabolism and mediate lipid production and organismal responses to changing environments. To test the hypothesis, Aim 1 will characterize PA interaction with the clock regulators by determining the lipid binding specificity to LHY, the amino acid residues involved in PA binding, and the intracellular location of the PA-LHY interaction using subcellular-specific PA biosensors and mass spectrometry. Aim 2 will address how altered PA metabolism entrains the circadian clock and mediates stress responses by identifying genes/enzymes responsible for producing PA species that alter clock function. Through quantifying the effect of cellular PA changes on the expression of genes involved in clock regulation, these data will be used to model how cellular PA changes lead to alterations in circadian rhythms and clock outputs. Aim 3 will determine how the circadian clock affects lipid metabolism by using clock mutants to assess how misalignments between internal circadian rhythms and the external environment affect lipid metabolism and accumulation. In addition, clock-targeted genes in lipid metabolism will be identified and tested for roles in the circadian regulation of lipid accumulation. The proposed studies will reveal new regulatory mechanisms for both the circadian clock and lipid metabolism and will advance the current understanding of the interplay between these two pathways. The results are relevant to human health because PA is a lipid mediator involved in mammalian clock regulation and various pathological processes, and the basic molecular mechanism of the clock is conserved between plants and humans. Therefore, the impact of the proposed work is to advance foundational knowledge for the molecular interconnection between lipid metabolism and the clock in eukaryotes, and the information has the potential for future strategies for understanding and mitigating metabolic and physiological dysfunctions associated with clock disruptions.

项目总结 生物钟的失调和扰乱会导致代谢和生理功能障碍。时钟调整时间 新陈代谢，而新陈代谢活动反馈影响昼夜节律，而时钟之间的这种相互作用 新陈代谢协调生理。然而，一个主要的知识差距是对 新陈代谢影响时钟功能的机制。这项拟议的研究的目标是阐明分子 生物钟和脂类代谢通过相互作用和相互作用而相互联系的机制 利用模式生物拟南芥对脂质调节剂和主要时钟调节剂之间的调节。这个 最近的研究结果支持了拟议研究的可行性，即中枢甘油脂代谢中间体， 磷脂酸(PA)，直接与时钟转录因子LHY(晚期延长的下胚轴)结合， PA代谢活动的操纵改变了时钟输出，时钟的中断扰乱了体内的脂质积累 拟南芥。假设PA-LHY相互作用起到细胞管道的作用，整合生物钟 与脂肪代谢有关，并调节脂肪的产生和机体对变化环境的反应。要测试 假设，目标1将通过确定脂质结合特异性来表征PA与时钟调节器的相互作用 对于LHY，涉及PA结合的氨基酸残基，以及PA-LHY相互作用的胞内定位 亚细胞特有的PA生物传感器和质谱学。目标2将解决PA新陈代谢变化如何影响 生物钟，并通过识别负责产生PA物种的基因/酶来调节应激反应 更改时钟功能。通过量化细胞PA变化对时钟相关基因表达的影响 这些数据将被用来模拟细胞PA变化如何导致昼夜节律和时钟的变化 产出。目标3将通过使用时钟突变来评估生物钟如何影响脂肪代谢，从而确定生物钟如何影响脂肪代谢。 内部昼夜节律和外部环境之间的失调会影响脂质代谢和 积累。此外，还将识别和测试脂质代谢中的时钟靶向基因在昼夜节律中的作用。 调节脂肪堆积。拟议中的研究将揭示两种生物钟的新调节机制 和脂质代谢，并将促进目前对这两个途径之间相互作用的理解。结果是 与人类健康有关，因为PA是一种参与哺乳动物生物钟调节和各种 病理过程中，时钟的基本分子机制在植物和人类之间是保守的。 因此，提出的工作的影响是推进分子互连的基础知识 在真核生物中脂代谢和时钟之间的关系，这一信息有可能成为未来的战略 了解和缓解与生物钟紊乱相关的代谢和生理功能障碍。