KLF15 and circadian regulation of alcohol-induced liver injury

描述（由申请人提供）：本提案描述了一项研究计划，该研究计划将对称为kruppel样因子15的转录因子在酒精诱导的肝损伤的昼夜节律调节中的作用提供新的见解。在物种中，生理过程是由昼夜节律调节的；一种以24小时为周期的自然生理和行为模式。有充分证据表明，急性和慢性饮酒对人类和其他动物的时间生物学过程都有不利影响。此外，一些研究表明，酒精对健康的一些负面影响可能与正常生理时间的中断有关。相反，昼夜节律紊乱也可能影响酒精介导的行为和组织损伤。尽管付出了相当大的努力，酒精代谢和昼夜节律生物学之间的分子联系仍然知之甚少。我们实验室的初步研究已经确定kruppel样因子15是一个昼夜节律因子，是酒精代谢的重要介质。我们发现，kruppel样因子15的表达，与参与酒精代谢的两种关键酶（线粒体醛脱氢酶2和色氨酸2,3双加氧酶）的表达一样，具有昼夜节律性。此外，这两种酶的昼夜节律在kruppel样因子15敲除小鼠中被废除，这些动物在酒精喂养的反应中出现肝损伤。在这个应用程序中，我们希望实现几个目标。首先，我们希望确定酒精是如何降低KLF15表达的。其次，我们将确定改变肝脏中克虏伯样因子15的水平如何影响动物耐受酒精暴露的能力。最后,我们

DESCRIPTION (provided by applicant): 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.