CDK8 regulation in alcoholic liver disease

CDK8在酒精性肝病中的调节

基本信息

批准号：
8678167
负责人：
Fajun James Yang
金额：
$ 24.01万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8678167
关键词：
ADD-1 protein Acetylation Affect Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Biochemical Bioinformatics CDC2 Protein Kinase Cell Cycle Regulation Cell Nucleus Centers for Disease Control and Prevention (U.S.)Cessation of life Cirrhosis Complex Cultured Cells Cyclin-Dependent Kinases Data Development Disease Doctor of Philosophy Down-Regulation Endoplasmic Reticulum Ethanol Ethanol Metabolism Fatty Liver Fibrosis Genes Genetic Transcription Glycogen Synthase Kinase 3 Health Hepatic Hepatocyte Histone Deacetylase Human In Vitro Knock-out Lead Lipids Liver Lysine MED15 Mediator of activation protein Membrane Modification Molecular Molecular Biology Mus Mutate N-terminal Nature Nuclear Organ Outcome Pharmaceutical Preparations Phosphorylation Physiological Play Post-Translational Protein Processing Primary carcinoma of the liver cells Principal Investigator Proteins Proteolytic Processing Public Health Recruitment Activity Regulation Research Role Series Serum Site Staging Steatohepatitis Surface Testing Therapeutic Transcription Coactivator Transcription Factor 3 Translating United States Yang adiponectin base chronic alcohol ingestion citrate carrier cofactor cyclin C effective therapy fatty acid biosynthesis human CDK2 protein human disease in vivo in vivo Model innovation insight lipid biosynthesis liver injury mouse model multicatalytic endopeptidase complex novel novel therapeutic intervention problem drinker protein complex public health relevance research study transcription factor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a leading cause of liver-related deaths in the United States. Currently there is no effective therapy. This is due to the lack of complete mechanistic understanding on how ethanol metabolism causes organ damage. A common feature of ALD is excessive lipid accumulation in hepatocytes, which is driven by alcohol-induced de novo lipogenesis. As a key transcriptional activator of lipogenic genes, sterol regulatory element-binding protein-1c (SREBP-1c) is activated in ALD. Thus, understanding the regulation of SREBP-1c activation will provide not only novel insights into the molecular mechanisms responsible for the development of ALD, but also therapeutic opportunities for treating ALD. Recently, we found CDK8, a subunit of the Mediator cofactor complex, as a negative regulator of de novo lipogenesis. Mechanistically, CDK8 phosphorylates nuclear form of SREBP-1c, promoting degradation of this transcription factor. Interestingly, our preliminary data show that hepatic CDK8 proteins are decreased in mouse models of ALD and in vitro, suggesting that CDK8 is directly or indirectly targeted by ethanol metabolism. However, it is unknown how ethanol down-regulates CDK8. The central hypothesis of the project is that alcohol abuse causes down- regulation of CDK8, and as a result, nuclear SREBP-1c is accumulated, contributing to ALD. To test the hypothesis, a series of in vivo and in vitro experiments are proposed to determine the role of hepatic CDK8 in the development of ALD and to elucidate the regulatory mechanisms of alcohol- induced down-regulation of CDK8. The long-term objective of the project is to determine the function and regulation of CDK8 in ALD. This application is not only significantly relevant to public health, but also highly innovative an will have positive impacts to the field of alcoholic diseases.

描述（由申请人提供）：酒精性肝病（ALD）是美国与肝有关的主要原因。目前没有有效的疗法。 This is due to the lack of complete mechanistic understanding on how ethanol metabolism causes organ damage. A common feature of ALD is excessive lipid accumulation in hepatocytes, which is driven by alcohol-induced de novo lipogenesis.作为脂肪生成基因的关键转录活化剂，固醇调节元素结合蛋白1C（SREBP-1C）被ALD激活。因此，了解SREBP-1C激活的调节不仅将提供对负责ALD发展的分子机制的新见解，而且还提供了治疗ALD的治疗机会。最近，我们发现CDK8是介体辅因子复合物的亚基，是从头脂肪生成的负调节剂。从机械上讲，CDK8磷酸化SREBP-1C的核形式，促进该转录因子的降解。有趣的是，我们的初步数据表明，在ALD和体外的小鼠模型中，肝CDK8蛋白降低，这表明CDK8是由乙醇代谢直接或间接靶向的。但是，尚不清楚乙醇如何下调CDK8。该项目的核心假设是酗酒会导致CDK8的下调，因此，核SREBP-1C积累了，对ALD造成了贡献。为了检验假设，提出了一系列体内和体外实验，以确定肝CDK8在ALD发展中的作用，并阐明酒精诱导的CDK8下调的调节机制。该项目的长期目标是确定ALD中CDK8的功能和调节。该应用不仅与公共卫生显着相关，而且具有高度创新性的A将对酒精疾病领域产生积极影响。