KLF15 and circadian regulation of alcohol-induced liver injury

KLF15 与酒精性肝损伤的昼夜节律调节

• 批准号: 8576602
• 负责人: Zhiyong Lin
• 金额: $ 35.66万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-05 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8576602
• 关键词: Acetaldehyde; Acute; Address; Affect; Alcohol abuse; Alcoholic Liver Diseases; Alcoholism; Alcohols; Ammonia; Animals; Behavior; Behavioral; Biological Process; Biology; ChIP-seq; Chronic; Chronotherapy; Circadian Rhythms; Coupled; Disease; Enzymes; Ethanol Metabolism; Exhibits; Family; Foundations; Gene Targeting; Genes; Genetic; Goals; Health; Hepatic; Hour; Human; Individual; Knockout Mice; Life; Liver; MAPK8 gene; Mediating; Mediator of activation protein; Metabolism; Mitochondria; Molecular; Mus; Organism; Pathway interactions; Patients; Pattern; Periodicity; Phenotype; Physiological; Physiological Processes; Plasma; Process; Regulation; Research; Role; Societies; Time; Tissues; Toxic effect; Transcription Factor AP-1; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophanase; Urea; Weight; Weight Gain; Wild Type Mouse; Zinc Fingers; alcohol effect; alcohol exposure; alcohol response; aldehyde dehydrogenases; base; cell injury; cellular development; chronic alcohol ingestion; combat; feeding; in vivo; insight; liver function; liver injury; loss of function; member; novel; reconstitution; research study; transcription factor; transcriptome sequencing

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.

描述（由申请人提供）：该提案描述了一项研究计划，该计划将为称为Kruppel样因子15的转录因子在酒精诱导的肝损伤的circadin调节中的作用提供新的见解。跨物种，生理过程由昼夜节律调节;一种自然的生理和行为模式，被计时到近24小时的周期。它已被充分记录，急性和慢性酒精消费对人类和其他动物的时间生物学过程的有害影响。此外，许多研究表明，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，像参与酒精代谢的两个关键酶，称为线粒体醛脱氢酶2和色氨酸2，3双加氧酶，表现出昼夜节律性。此外，这两种酶的昼夜节律在Kruppel样因子15敲除小鼠中被消除，并且这些动物响应于酒精喂养而发生肝损伤。在这个应用程序中，我们希望实现几个目标。首先，我们希望确定酒精如何降低KLF 15表达。其次，我们将确定如何改变肝脏中Kruppel样因子15水平影响动物耐受酒精暴露的能力。最后我们 试图了解Kruppel样因子15在正常条件下和对酒精喂养的反应中调控的基因的全谱。这些信息可以为开发针对酒精性肝病治疗的时间疗法提供平台。