Document text
Principal Investigator: Michael John Palladino
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $397,500
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Circadian rhythms are a critical component of behavioral and homeostatic function in nearly every organism on
Earth, including humans. Neurological diseases such as Alzheimer's, Parkinson's, and epilepsy are often
accompanied by disruptions in circadian rhythms. In turn, this can exacerbate neuropathology symptoms and
worsen quality of life by causing insomnia, fragmented sleep, daytime hypersomnia, and perturbation of
metabolism. In fact, the links between metabolism and circadian function are becoming increasingly apparent.
Several components of the core molecular clock are redox sensitive or transcriptionally modified by
metabolites like NADPH, and mitochondria are known to exhibit circadian rhythms. Drosophila are an excellent
model organism in which to study circadian rhythms at behavioral, genetic, and neuronal level, possessing a
vast genetic toolkit and highly standardized methodology for assaying rhythmicity. We recently established that
the stable Drosophila model for mitochondrial diseases such as Maternally Inherited Leigh Syndrome, termed
ATP6[1], exhibits profound arrhythmicity in sleep/wake behavioral patterns and in specific behaviors such as
egg laying and eclosion under constant conditions, making it an excellent model system in which to study the
mechanistic links between altered metabolism and circadian rhythms. Here, we propose to determine the
mechanism by which mitochondrial disease leads to rhythm disruption by probing the molecular clock's
transcription-translation feedback loop, examining the physiology of the circadian circuit at the neuronal level,
and elucidating the consequences of perturbed bioenergetics and redox state. Importantly, we have also
recently discovered a successful treatment for the neurological consequences of mitochondrial disease in the
ketogenic diet, including significant improvement in rhythmicity. Therefore, we propose in Aim 2 to determine
the scope and mechanism by which this dietary therapy improves circadian function by examining
bioenergetics and physiology of neurons and glia, ion channel modulation in circadian neurons, altered gene
expression in the circadian circuit, and effects on the core clock. Additionally, we have found via a preliminary
genetic screen that disruption of glycolysis and of the Krebs Cycle also have a negative impact on circadian
rhythms. For example, RNAi knockdown and classical null alleles of citrate synthase have extremely poor
rhythmicity. We propose in Aim 3 to use the power of the Drosophila genetic toolkit to identify novel modulators
of circadian function in critical metabolic pathways including glycolysis, the Krebs Cycle, ketone body and lipid
metabolism, amino acid and neurotransmitter synthesis, and others. Overall, this project will contribute
significantly to our understanding of the links between metabolism and circadian rhythms in health and
neurological disease, as well as open new therapeutic avenues based on diet and metabolic targets.
Terms: <AD dementia><ATP sensitive potassium channel><ATP sensitive potassium channel complex><After Care><After-Treatment><Aftercare><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amino Acids><Arrhythmia><Assay><Behavior><Behavioral><Bioassay><Bioenergetics><Biologic Models><Biological Assay><Biological Models><Brain><Brain Nervous System><Cardiac Arrhythmia><Cellular Regulation><Circadian Dysregulation><Circadian Rhythms><Citrate (si)-Synthase><Citrate Synthase><Citric Acid Cycle><Coenzyme II><Cyclicity><Degenerative Neurologic Disorders><Diabetes Mellitus><Diet><Diet therapy><Disease><Disease Progression><Disorder><Drosophila><Drosophila genus><Dysfunction><Earth><Electrophysiology><Electrophysiology (science)><Encephalon><Energy Supply><Environment><Enzyme Gene><Enzymes><Epilepsy><Epileptic Seizures><Epileptics><Exhibits><Feedback><Flies><Functional disorder><Future><Gene Expression><Gene Transcription><Genetic><Genetic Screening><Genetic Transcription><Glia><Glial Cells><Glycolysis><Health><Heart Arrhythmias><Hereditary><Human><Hypersomnias><Inherited><Insomnia><Insomnia Disorder><Intermediary Metabolism><Ion Channel><Ionic Channels><Ketone Bodies><Ketones><Kolliker's reticulum><Krebs Cycle><Lateral><Leigh Disease><Leigh Syndrome><Length of Life><Link><Lipids><Longevity><Mediating><Membrane Channels><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Pathway><Metabolic Processes><Metabolism><Methodology><Methods><Mitochondria><Mitochondrial Diseases><Mitochondrial Disorders><Model System><Modeling><Modern Man><Molecular><Molecular Probes><NAD phosphate><NAD(H) phosphate><NADH phosphate><NADP><NADPH><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Nervous System Physiology><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neurologic><Neurologic Degenerative Conditions><Neurologic Disorders><Neurologic Dysfunctions><Neurologic Effect><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurologic function><Neurological><Neurological Disorders><Neurological Manifestations><Neurological Signs and Symptoms><Neurological function><Neurons><Neurophysiology / Electrophysiology><Neurotransmitters><Nicotinamide-Adenine Dinucleotide Phosphate><Non-neuronal cell><Nonneuronal cell><Nyctohemeral Rhythm><Obesity><Organism><Oxidation-Reduction><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Paralysis Agitans><Parkinson><Parkinson Disease><Pattern><Periodicity><Physiology><Physiopathology><Planet Earth><Play><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Primary Parkinsonism><Primary Senile Degenerative Dementia><Process><Property><QOL><Quality of life><RNA Expression><RNA Interference><RNA Silencing><RNA interference screen><RNAi><RNAi screen><RNAi-based screen><Redox><Regulation><Rhythmicity><Role><Seizure Disorder><Seizures><Sequence-Specific Posttranscriptional Gene Silencing><Sleep><Sleep Fragmentations><Sleeplessness><Standardization><Subacute Necrotizing Encephalomyelitis><Subacute Necrotizing Encephalomyelopathy><Subacute Necrotizing Encephalopathy><Symptoms><System><TCA cycle><Testing><Thesaurismosis><Transcription><Translations><Tricarboxylic Acid Cycle><Triphosphopyridine Nucleotide><Twenty-Four Hour Rhythm><adiposity><aminoacid><cardiac pacemaker cell><cell growth regulation><circadian><circadian abnormality><circadian biology><circadian clock><circadian disruption><circadian disturbance><circadian dysfunction><circadian impairment><circadian pacemaker><circadian process><corpulence><daily biorhythm><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><diabetes><dietary><dietary therapy><diets><egg><electrophysiological><epilepsia><epileptogenic><experiment><experimental research><experimental study><experiments><fat metabolism><fly><fruit fly><healthy aging><healthy human aging><improved><keto diet><ketogenesis><ketogenic><ketogenic diet><ketogentic><knock-down><knockdown><life span><lifespan><lipid metabolism><living system><metabolism disorder><mitochondrial><mitochondrial dysfunction><model organism><molecular clock><nerve cement><nervous system function><neural manifestation><neurodegenerative illness><neurological disease><neurological dysfunction><neuronal><neuropathologic><neuropathological><neuropathology><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><nodal myocyte><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oxidation reduction reaction><pacemaker cell><patch clamp><pathophysiology><post treatment><primary degenerative dementia><response><senile dementia of the Alzheimer type><sensor><social role><therapeutic target><translation>