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Principal Investigator: MITCHELL A. LAZAR
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $556,221
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Circadian misalignment has deleterious effects on metabolism, and contributes to the obesity and diabetes epidemics in the United States. REV-ERB nuclear receptors link the circadian clock and metabolism, and the present proposal combines tissue-specific, genome-wide analysis of cistromes, transcriptomes, and the epigenome in novel mouse genetic models with sophisticated metabolic phenotyping to understand the physiological role of REV-ERBa and b in the generation and systemic coordination of central and hepatic circadian rhythms and metabolism. Specific Aim 1 is to determine the cell autonomous and non-cell autonomous roles of hepatic REV-ERBa and b in liver circadian rhythms and metabolism. We hypothesize that REV-ERBs have cell-autonomous as well as non-cell autonomous functions in hepatocytes. Preliminary characterization of adult mice after hepatocyte REV-ERB double knockout (HepDKO) has demonstrated the cell-autonomous role of REV-ERBs in liver circadian rhythms and also revealed genes that do not lose circadian rhythmicity upon REV-ERB deletion. The underlying mechanisms and specialized metabolic functions will be determined using integrative functional genomics, proteomics, and metabolic phenotyping. Specific Aim 2 is to elucidate the molecular mechanisms by which hepatocyte REV-ERBs control circadian rhythms in non-hepatocytic liver cells. In addition to hierarchical (cell-autonomous and non-cell autonomous) regulation of peripheral clocks, we hypothesize that there is communication between peripheral clocks in difference cell types with an organ. Preliminary data demonstrate that hepatocyte REV-ERBs control circadian rhythms in non-hepatocytes. The scope and underlying mechanisms will be determined using integrative genomics and metabolomics. In Specific Aim 3 we will determine the role of hypothalamic REV-ERBs in the regulation of circadian behavior and metabolism. We hypothesize that hypothalamic REV-ERBs centrally control circadian
behavior as well as peripheral metabolism, and this is borne out by preliminary analysis of mice with deletion of REV-ERBs in the suprachiasmatic nucleus (SCN) as well as other mice with REV-ERB deletion in non-SCN neurons. Cistromic, transcriptomic, and epigenomic analysis will be used to determine the underlying molecular mechanisms. We will also utilize novel mouse models to test the desyncrony hypothesis of metabolic stress resulting from lack of coordination between biological clocks and environmental zeitgeberes. Together, the studies will lead to a more fundamental understanding of the links between circadian rhythm and metabolism that underlie
the mechanism by which circadian misalignment exacerbates metabolic dysfunction, obesity, and diabetes.
Terms: <21+ years old><ATAC sequencing><ATAC-seq><ATACseq><Abnormal Assessment of Metabolism><Abnormal coordination><Adult><Adult Human><Antigenic Determinants><Assay for Transposase-Accessible Chromatin using sequencing><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Behavior><Behavior Control><Behavioral Manipulation><Binding><Binding Determinants><Biological Clocks><Biology><Body Tissues><Cardiovascular Diseases><Cell Body><Cell Nucleus><Cells><ChIP Sequencing><ChIP assay><ChIP-seq><ChIPseq><Circadian Dysregulation><Circadian Rhythms><Circadian desynchrony><Circadian gene expression><Co-ordination disorder><Communication><Coordination Disorder><Cyclicity><Data><Diabetes Mellitus><Dorsal><Dyscoordination><Enhancers><Epidemic><Epitopes><Experimental Genetics><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic Models><Genetic Transcription><Genetic study><Genomics><Goals><Hepatic><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Homeostasis><Hypothalamic structure><Hypothalamus><Incoordination><Intermediary Metabolism><Knock-out><Knockout><Knowledge><Laboratories><Lack of Coordination><Learning><Ligands><Link><Liver><Liver Cells><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolic Studies><Metabolic dysfunction><Metabolic stress><Metabolism><Metabolism Studies><Mice><Mice Mammals><Molecular><Molecular Interaction><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nuclear Receptors><Nucleus><Nyctohemeral Rhythm><Obesity><Organ><Periodicity><Peripheral><Persons><Phenotype><Physiologic><Physiological><Physiological Homeostasis><Physiology><Proteomics><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Regulation><Repression><Rhythmicity><Role><Testing><Thesaurismosis><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription Repressor><Transcription factor genes><Transcriptional Repressor><Twenty-Four Hour Rhythm><United States><Work><adiposity><adulthood><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><behavioral control><body clock><cardiovascular disorder><cell type><chromatin immunoprecipitation><chromatin immunoprecipitation-sequencing><circadian><circadian abnormality><circadian biology><circadian clock><circadian desynchronization><circadian disruption><circadian disturbance><circadian dysfunction><circadian impairment><circadian misalignment><circadian pacemaker><circadian process><circadian regulation><combat><corpulence><daily biorhythm><day shift><diabetes><epigenome><epigenomics><functional genomics><genetic repressor><genome scale><genome wide analysis><genome wide studies><genome-wide><genome-wide analysis><genome-wide identification><genomewide><global gene expression><global transcription profile><hepatic body system><hepatic organ system><hypothalamic><innovate><innovation><innovative><insight><internal clock><intrahepatic><metabolic abnormality assessment><metabolic phenotype><metabolism disorder><metabolism measurement><metabolomics><metabonomics><metabotype><mouse genetics><mouse model><murine model><neuronal><new approaches><night shift><night work><novel><novel approaches><novel strategies><novel strategy><receptor><shift work><shiftwork><social role><suprachiasmatic nucleus><transcription factor><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcriptomics>