KLF15 and circadian regulation of alcohol-induced liver injury

KLF15 与酒精性肝损伤的昼夜节律调节

基本信息

批准号：
9000080
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
项目类别：
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/9000080
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 novel therapeutics reconstitution research study transcription factor transcriptome sequencing

项目摘要

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，该计划将提供新的见解，以了解称为Kruppel样因子15在酒精诱导的肝损伤的Circadin调节中的作用。在整个物种中，生理过程受昼夜节律调节。天然的生理和行为模式，定时为24小时。已经有充分的文献证明，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，许多研究表明，某些酒精的负面健康后果可能与正常生理时机的破坏有关。相反，昼夜节律破坏也可能影响酒精介导的行为和组织损害。尽管付出了很大的努力，但酒精代谢与昼夜节律生物学之间的分子联系仍然很少理解。来自我们实验室的初步研究已经确定Kruppel样因子15是昼夜节律因素，它是酒精代谢的重要介体。我们发现，类似Kruppel的因子15表达，例如两种参与酒精代谢的关键酶，称为线粒体醛醛脱氢酶2和色氨酸2,3二氧酶，表现出昼夜节律的节奏性。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，这些动物会因饮酒而产生肝脏损害。在此应用程序中，我们希望实现多个目标。首先，我们希望确定酒精如何降低KLF15的表达。其次，我们将确定肝脏中克鲁诗样系数15水平的改变如何影响动物耐受酒精暴露的能力。最后，我们寻求了解在正常条件下和饮酒的响应下，由Kruppel样因子15调节的全基因。这样的信息可以提供一个平台，以开发针对酒精性肝病治疗的时间疗法。