This proposal describes a research plan that will offer novel insights into the role of a transcription factor termed Kruppel-like factor 15 in the circadin regulation of alcohol- induced liver injury. Across species, physiological processes are regulated by a circadian rhythm;a natural physiological and behavioral pattern that is timed to a near 24-hour period. It has been well documented that both acute and chronic alcohol consumption have detrimental effects on chronobiological processes in humans and other animals. Further, a number of studies indicate that some of alcohol's negative health consequences may be related to a disruption of normal physiological timing. Conversely, circadian rhythm disruption may also impact on alcohol mediated behavior and tissue damage. Despite considerable effort, the molecular connection between alcohol metabolism and circadian biology remain poorly understood. Preliminary studies from our lab have identified Kruppel-like factor 15 as a circadian factor that is an important mediator of alcohol metabolism. We found that Kruppel-like factor 15 expression, like that of two critical enzymes involved in alcohol metabolism termed mitochondrial aldehyde dehydrogenase 2 and tryptophan 2,3 dioxygenase, exhibit circadian rhythmicity. Moreover, the circadian rhythm of these two enzymes is abolished in Kruppel-like factor 15 knockout mice and these animals develop liver damage in response to alcohol feeding. In this application, we hope to accomplish several goals. First, we hope to determine how alcohol reduces KLF15 expression. Second, we will determine how altering Kruppel-like factor 15 levels in the liver affects the animals ability to tolerate alcohol exposure. Finally, we seek to understand the full spectrum of gene regulated by Kruppel-like factor 15 under normal conditions and in response to alcohol feeding. Such information may provide a platform to develop chronotherapies directed at the treatment of alcoholic liver disease.
Given the deleterious effects that alcohol abuse and alcoholism exert on individuals and our society, it is important to gain a better understanding of factors mediating physiological responses to alcohol. Studies in this proposal aim to address the regulation of alcohol metabolism by a genetic factor Kruppel- like factor 15. The results may provide the foundation for novel chronotherapeutic approaches to ameliorate the detrimental effects of chronic alcohol use.
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