Circadian rhythms and alcohol in the BMAL1 knockout rat

点击翻译按钮获取中文摘要

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.