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Principal Investigator: XUEMIN WANG
Organization: UNIVERSITY OF MISSOURI-ST. LOUIS
Fiscal Year: 2024
Award: $295,695
Funding agency: National Institute of General Medical Sciences
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.
Terms: <Address><Affect><Amino Acids><Arabidopsis><Arabidopsis thaliana><Assay><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biological Assay><Biosensor><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Nucleus><Cell Proliferation><Cell Signaling><Cell model><Cells><Cellular Proliferation><Cellular model><ChIP assay><Circadian Dysregulation><Circadian Rhythms><Darkness><Data><Disease><Disorder><Dysfunction><Environment><Enzyme Gene><Enzymes><Eukaryota><Eukaryote><Feedback><Fostering><Functional disorder><Future><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetics-Mutagenesis><Glycerolipid Metabolism><Glycerolipid Metabolism Pathway><Goals><Health><Homeostasis><Human><Hypocotyl><Intermediary Metabolism><Intracellular Communication and Signaling><Knowledge><Lead><Light><Link><Lipid Binding><Lipids><Liposomal><Liposomes><Location><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Pathway><Metabolic Processes><Metabolic dysfunction><Metabolism><Mission><Modeling><Modern Man><Molecular><Molecular Interaction><Monitor><Mouse-ear Cress><Mutagenesis><Mutagenesis Molecular Biology><Mutation><NIH><National Institutes of Health><Nucleus><Nyctohemeral Rhythm><Outcome><Output><Pathologic Processes><Pathological Processes><Pathway interactions><Pb element><Phosphatidic Acid><Photoradiation><Physiologic><Physiological><Physiological Homeostasis><Physiology><Physiopathology><Plants><Process><Production><RNA Expression><Regulation><Regulator Genes><Research><Role><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Surface Plasmon Resonance><Testing><Thesaurismosis><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Regulatory Elements><Twenty-Four Hour Rhythm><United States National Institutes of Health><Work><aminoacid><biological adaptation to stress><biological sensor><biological signal transduction><chromatin immunoprecipitation><circadian><circadian abnormality><circadian clock><circadian disruption><circadian disturbance><circadian dysfunction><circadian impairment><circadian pacemaker><circadian process><circadian regulation><daily biorhythm><data mining><datamining><day length><experiment><experimental research><experimental study><experiments><fat metabolism><genome editing><genome mutation><genomic editing><heavy metal Pb><heavy metal lead><improved><in vivo><innovate><innovation><innovative><insight><lipid bound><lipid mediator><lipid metabolism><lipidomics><metabolism disorder><model organism><mutant><novel><pathophysiology><pathway><reaction; crisis><regulatory gene><response><screening><screenings><social role><stress response><stress; reaction><trans acting element><transcription factor>