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

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

项目成果

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SHANNON MARIE BAILEY其他文献

SHANNON MARIE BAILEY的其他文献

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{{ truncateString('SHANNON MARIE BAILEY', 18)}}的其他基金

Circadian and mitochondrial dysfunction in alcohol-related liver disease
酒精相关性肝病中的昼夜节律和线粒体功能障碍
  • 批准号:
    10667861
  • 财政年份:
    2023
  • 资助金额:
    $ 21.35万
  • 项目类别:
Circadian rhythms and alcohol in the BMAL1 knockout rat
BMAL1 敲除大鼠的昼夜节律和酒精
  • 批准号:
    10707005
  • 财政年份:
    2022
  • 资助金额:
    $ 21.35万
  • 项目类别:
Molecular circadian clocks and alcohol-induced liver injury
分子生物钟和酒精性肝损伤
  • 批准号:
    9759734
  • 财政年份:
    2018
  • 资助金额:
    $ 21.35万
  • 项目类别:
Alcohol-Induced Mitochondrial Dysfunction and the Hepatocyte Clock
酒精引起的线粒体功能障碍和肝细胞时钟
  • 批准号:
    9280738
  • 财政年份:
    2016
  • 资助金额:
    $ 21.35万
  • 项目类别:
Hepatocyte Clock and Alcoholic Fatty Liver Injury
肝细胞时钟与酒精性脂肪肝损伤
  • 批准号:
    8144478
  • 财政年份:
    2010
  • 资助金额:
    $ 21.35万
  • 项目类别:
Hepatocyte Clock and Alcoholic Fatty Liver Injury
肝细胞时钟与酒精性脂肪肝损伤
  • 批准号:
    8065283
  • 财政年份:
    2010
  • 资助金额:
    $ 21.35万
  • 项目类别:
Alcoholic Liver Dysfunction Potentiation by Hyperlipidemia and Cigarette Smoke
高脂血症和吸烟加剧酒精性肝功能障碍
  • 批准号:
    8316433
  • 财政年份:
    2009
  • 资助金额:
    $ 21.35万
  • 项目类别:
Alcoholic Liver Dysfunction Potentiation by Hyperlipidemia and Cigarette Smoke
高脂血症和吸烟加剧酒精性肝功能障碍
  • 批准号:
    7932863
  • 财政年份:
    2009
  • 资助金额:
    $ 21.35万
  • 项目类别:
Alcoholic Liver Dysfunction Potentiation by Hyperlipidemia and Cigarette Smoke
高脂血症和吸烟加剧酒精性肝功能障碍
  • 批准号:
    7798912
  • 财政年份:
    2009
  • 资助金额:
    $ 21.35万
  • 项目类别:
Alcoholic Liver Dysfunction Potentiation by Hyperlipidemia and Cigarette Smoke
高脂血症和吸烟加剧酒精性肝功能障碍
  • 批准号:
    8127680
  • 财政年份:
    2009
  • 资助金额:
    $ 21.35万
  • 项目类别:

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