KLF15 and circadian regulation of alcohol-induced liver injury

描述(由申请人提供)：这项提案描述了一项研究计划，该计划将为一种名为Kruppel-like factor15的转录因子在酒精诱导的肝损伤的循环调节中的作用提供新的见解。在物种之间，生理过程受昼夜节律的调节；这是一种自然的生理和行为模式，时间接近24小时。有充分的证据表明，急性和长期饮酒都会对人类和其他动物的时间生物学过程产生有害影响。此外，一些研究表明，酒精对健康的一些负面影响可能与扰乱正常的生理时序有关。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。尽管做出了相当大的努力，但酒精代谢和昼夜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发现，Kruppel样因子15是一种昼夜节律因子，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双加氧酶一样，表现出昼夜节律性。此外，在Kruppel样因子15基因敲除小鼠中，这两种酶的昼夜节律被取消，这些动物因酒精喂养而出现肝脏损伤。在这个应用程序中，我们希望实现几个目标。首先，我们希望确定酒精如何降低KLF15的表达。其次，我们将确定改变肝脏中Kruppel样因子15水平如何影响动物对酒精暴露的耐受能力。最后，我们 寻求了解在正常情况下和在酒精喂养下受Kruppel样因子15调控的基因的全谱。这些信息可能为开发针对酒精性肝病治疗的时辰疗法提供一个平台。

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.