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Circadian rhythms and alcohol in the BMAL1 knockout rat

BMAL1 敲除大鼠的昼夜节律和酒精

基本信息

批准号：
10707005
负责人：
SHANNON MARIE BAILEY
金额：
$ 17.63万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10707005
关键词：
ARNTL gene Acceleration Address Alcohol consumption Alcohol dependence Alcoholic Liver Diseases Alcohols Animal Model Animals Bioenergetics Biological Process Brain Injuries CRISPR/Cas technology Cause of Death Cell physiology Cells Chronotherapy Circadian Dysregulation Circadian Rhythms Clinical Complex Depressed mood Development Disease Dose Ensure Environmental Risk Factor Ethanol toxicity Etiology Exhibits Feedback Fetal Alcohol Syndrome Functional disorder Gastrointestinal Diseases Genes Genetic Genetic Transcription Genotype Goals Health Heart Diseases Hepatic Histopathology Human Immune System Diseases Impairment Inflammatory Injury Intestinal permeability Kidney Diseases Knock-out Knowledge Liver Liver Mitochondria Liver diseases Malignant Neoplasms Medical Mental Health Messenger RNA Metabolic Metabolism Methods Mitochondria Mitochondrial DNA Modeling Molecular Molecular Target Mus Normal tissue morphology Nutrient Organ Outcome Outcomes Research Output Pathologic Pathology Pathway interactions Patients Physiological Physiology Production Publishing Rattus Reactive Oxygen Species Research Research Personnel Research Project Grants Resolution Respiration Respiratory physiology Rest Risk Risk Factors Role Spirometry Stimulus Stress System Technology Testing Time Tissues Transcript Transcription Coactivator Transcriptional Regulation Ulcer United States Variant Work alcohol risk chronic alcohol ingestion circadian circadian biology clinically relevant drug development effective therapy experimental study genome editing glycogen metabolism high reward knockout gene lipid metabolism liver function liver injury liver metabolism metabolomics molecular clock novel oxidative damage pre-clinical preclinical study preventable death problem drinker respiratory tissue injury translational impact

项目摘要

PROJECT SUMMARY Liver disease is the number one cause of death from long-term heavy alcohol drinking in the United States. While dose and duration of alcohol consumption are well-accepted risk factors for disease, it is clear that the etiology of alcohol-related liver disease (ALD) is highly complex, involving many still unknown genetic, metabolic, and environmental factors. This complexity also likely explains why there are so few effective therapies for treating ALD. Therefore, a major unanswered question for the alcohol field is – what additional environmental factors, metabolic impairments, and/or molecular disturbances are required for liver pathology to occur in the alcohol consumer? A vital temporal integrator of environmental stimuli, metabolism, and cellular transcriptional control is the circadian system. At the cellular level, 24-h circadian rhythms are driven by a transcriptional-translational feedback loop system. This molecular clock mechanism involves activation of core clock genes and many downstream clock-output genes by the transcriptional activators BMAL1 and CLOCK. This molecular clock mechanism ensures that specific cellular and biological processes occur at the correct time of day. Accumulating evidence shows that circadian rhythm disruption worsens tissue function and injury in animals and humans consuming alcohol. Despite these new findings, the mechanistic understanding of how this occurs is very limited. This current proposal addresses a critical target of alcohol toxicity – the mitochondrion. Even though multiple studies have shown that alcohol severely impairs mitochondrial function, there have not been rigorous studies examining the impact of circadian disruption on temporal control of hepatic mitochondrial function in the alcohol consumer. We hypothesize that circadian disruption worsens alcohol-related impairments in hepatic mitochondrial bioenergetic function and increases tissue injury. To test this hypothesis, we will use an exciting new animal model, the Bmal1 knockout rat – the first rat model of a global clock gene knockout developed with CRISPR/Cas9 genome editing technology. In Aim 1, we will determine the role of Bmal1 in the temporal control of 24-h physiologic, metabolic, and molecular rhythms in alcohol-fed rats. In Aim 2, we will determine the role Bmal1 in alcohol-related mitochondrial bioenergetic dysfunction and liver injury. Successful completion of these studies will provide novel information regarding the interaction of the circadian system and alcohol on tissue and mitochondrial function and pathology. The knowledge gained from this work also has the ability to influence multiple scientific fields and facilitate development of novel chronotherapy-based approaches for treating patients suffering from ALD and other related liver diseases.

项目总结