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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要生物钟的失调和破坏会导致代谢和生理功能障碍。时钟调节新陈代谢，而代谢活动反馈影响昼夜节律，以及时钟之间的相互作用新陈代谢协调生理学。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。拟议研究的目标是阐明分子生物钟和脂质代谢通过相互作用和倒数相互关联的机制使用模式生物拟南芥进行脂质介质和主要时钟调节器之间的调节。这最近的发现支持了拟议研究的可行性，即中央甘油脂代谢中间体，磷脂酸（PA），直接与时钟转录因子LHY（LATE ELONGATED HYPOCOTYL）结合， PA 代谢活动的操纵会改变时钟输出，而时钟的破坏会扰乱体内的脂质积累拟南芥。假设 PA-LHY 相互作用充当整合生物钟的细胞管道与脂质代谢相关，并介导脂质产生和机体对不断变化的环境的反应。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使用 LHY、参与 PA 结合的氨基酸残基以及 PA-LHY 相互作用的细胞内位置亚细胞特异性 PA 生物传感器和质谱分析。目标 2 将解决改变 PA 代谢如何影响生物钟并通过识别负责产生 PA 物种的基因/酶来介导应激反应改变时钟功能。通过量化细胞 PA 变化对时钟相关基因表达的影响调节，这些数据将用于模拟细胞 PA 变化如何导致昼夜节律和时钟的改变输出。目标 3 将通过使用时钟突变体来评估生物钟如何影响脂质代谢内部昼夜节律与外部环境之间的失调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。拟议的研究将揭示生物钟的新调节机制和脂质代谢，并将促进目前对这两种途径之间相互作用的理解。结果与人类健康相关，因为 PA 是一种脂质介质，参与哺乳动物的时钟调节和各种病理过程，时钟的基本分子机制在植物和人类之间是保守的。因此，拟议工作的影响是推进分子互连的基础知识脂质代谢和真核生物时钟之间的关系，这些信息有可能成为未来的策略了解和减轻与时钟中断相关的代谢和生理功能障碍。