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: 10185527
• 负责人: XUEMIN WANG
• 金额: $ 31.79万
• 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/10185527
• 关键词: Address; Affect; Amino Acids; Animal Model; Arabidopsis; Binding; Biological Assay; Biosensor; Cell Nucleus; Cell Proliferation; Cell model; Cells; Circadian Dysregulation; Circadian Rhythms; Data; Disease; Environment; Enzymes; Eukaryota; Feedback; Fostering; Foundations; Functional disorder; Future; Gene Expression; Genes; Genetic Transcription; Glycerolipid Metabolism Pathway; Goals; Health; Homeostasis; Human; Hypocotyl; Knowledge; Lead; 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; base; 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; 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.

项目摘要 昼夜节律的未对准和破坏导致代谢和生理功能障碍。时钟调节 代谢，而代谢活动反馈以影响昼夜节律，而时钟之间的这种相互作用 并代谢协调生理学。但是，一个主要的知识差距是对 代谢影响时钟功能的机制。拟议的研究的目的是阐明分子 昼夜节律时钟和脂质代谢通过相互作用和相互互动互连的机制 使用模型有机体拟南芥之间的脂质介质和主要时钟调节剂之间的调节。这 拟议研究的可行性得到了最近的发现，即中央甘油代谢中间体， 磷脂酸（PA），直接与时钟转录因子Lhy（晚期伸长式下胚轴）结合， 对PA-量代谢活动的操纵改变了时钟输出，并破坏了时钟的干扰脂质积累 拟南芥。假设是Pa-lhy相互作用是整合昼夜节律的细胞导管 随着脂质代谢并介导脂质产生和对不断变化的环境的有机反应。测试 假设，AIM 1将通过确定脂质结合特异性来表征PA与时钟调节剂的相互作用 到Lhy，使用参与PA结合的氨基酸残基，以及使用PA-LHY相互作用的细胞内位置 亚细胞特异性PA生物传感器和质谱法。 AIM 2将解决变化的PA代谢如何纳入 昼夜节律时钟并通过识别负责产生PA物种的基因/酶来介导压力反应 更改时钟功能。通过量化细胞PA的影响对涉及时钟的基因表达的影响 调节，这些数据将用于建模细胞PA的变化如何导致昼夜节律的改变 输出。 AIM 3将通过使用时钟突变体评估如何评估昼夜节律时钟如何影响脂质代谢 内部昼夜节律与外部环境之间的不对对准会影响脂质代谢和 积累。此外，将鉴定并测试脂质代谢中的时钟靶向基因在昼夜节律中的作用 调节脂质积累。拟议的研究将揭示两个昼夜节律的新调节机制 和脂质代谢，并将提高对这两种途径之间相互作用的当前理解。结果 与人类健康有关，因为PA是参与哺乳动物时钟调节的脂质介质和各种 病理过程，时钟的基本分子机制是植物和人之间的保守。 因此，提出的工作的影响是提高分子互连的基础知识 在脂质代谢和真核生物中的时钟之间，该信息具有未来策略的潜力 了解和减轻与时钟中断相关的代谢和生理功能障碍。