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22368scr 6ed1c8875e46936by Hannah Buckelew

Shannon Bailey, Ph.D., Professor, Molecular and Cellular Pathology, Chair, UAB Institutional Animal Care and Use Committee (IACUC), has been awarded an R01 grant funding her research on circadian and mitochondrial dysfunction in alcohol-related liver disease. The grant, from the National Institute on Alcohol Abuse and Alcoholism of the NIH, is funded at $2.35 million over five years, through 2028.

Alcohol use is among the top 10 causes of preventable death in the United States, with alcohol-related liver disease (ALD) being the number one cause of death from alcohol use.

Circadian rhythm disruption has emerged as an important new risk factor in ALD. Circadian rhythms are regulated through external environmental factors and internal cellular signals, or the molecular clock. At the cellular level, 24-hour rhythms are driven by a transcriptional-translational feedback loop to ensure specific metabolic processes occur at the correct time of day.

“Proper circadian timing is critical for maintaining health, while circadian disruption increases disease risk,” Bailey says. “While there is growing interest in circadian disruption, only a handful of studies have investigated interactions of the circadian system and alcohol on peripheral tissues and pathology.”

Mitochondria are also a key player in the pathophysiology of liver disease, with growing recognition that some mitochondrial functions exhibit 24-hour rhythms regulated by the molecular clock. Given this information, Bailey’s team is testing the new hypothesis that, in the alcohol consumer, loss in circadian control over mitochondrial bioenergetics function is a significant challenge to liver health.

The goal of the project is to understand how chronic alcohol consumption disrupts diurnal changes in liver mitochondrial function by defining the roles of different molecular circadian clock genes in alcohol-induced mitochondrial dysfunction and testing whether normalizing function of the molecular clock during alcohol consumption lessens mitochondrial damage and alcohol-associated liver disease.

“Our studies are significantly impactful as they move beyond investigating the canonical transcriptional clock and instead focus on circadian impacts on function and pathology,” Bailey says.

This study will continue Bailey’s previous R21 grant to study whether disruptions in circadian rhythm can negatively influence liver health and whether these disruptions are risk factors for ALD. Bailey’s previous proposal analyzed the novel concept that circadian disruption presented an additional challenge to mitochondrial function and liver health in the alcohol consumer.

Bailey’s UAB collaborators on this R01 grant include Sameer Al Diffalha, M.D., Associate Professor, Division of Anatomic Pathology, and Scott Ballinger, Ph.D., Professor, Associate Dean, Faculty Affairs, Heersink School of Medicine, Division of Molecular and Cellular Pathology, Karen Gamble, Ph.D., Tate Jordan Thomas Professor Vice Chair for Basic Research, and Jodi Paul, Ph.D., Scientist II, both in the Department of Psychiatry and Behavioral Neurobiology.

“We are hopeful our pre-clinical studies will stimulate new discoveries for mitochondrial and chronobiology-based therapies for treating patients with alcohol-associated liver disease and other serious liver diseases.”