Role of Arginine Methylation in Alcohol Pathogenesis

精氨酸甲基化在酒精发病机制中的作用

• 批准号: 10625370
• 负责人: Irina Tikhanovich
• 金额: $ 42.52万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-05 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625370
• 关键词: 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine; Affect; Alcohol-Induced Disorders; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Animal Feed; Animals; Apoptosis; Arginine; Binding; Cell Cycle; Cell Proliferation; Cell Survival; Cessation of life; ChIP-seq; Cirrhosis; Clinical; Data; Defect; Disease; Disease Progression; Enzymes; Epigenetic Process; Equilibrium; Fibrosis; Future; Gene Expression; Genes; Genetic; Glycine decarboxylase; Goals; Hepatocyte; Histones; In Vitro; Individual; Inflammation; Injections; Knock-out; Knockout Mice; Lipids; Liver; Liver diseases; LoxP-flanked allele; Mass Spectrum Analysis; Measures; Mediating; Methylation; Modification; Mus; Nature; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Post-Translational Protein Processing; Predisposition; Proliferating; Protein Dephosphorylation; Protein-Arginine N-Methyltransferase; Proteins; Regulation; Role; Sampling; Serum; Severity of illness; Specificity; System; Testing; Therapeutic; alcohol exposure; alcohol involvement; alcohol prevention; alcohol sensitivity; demethylation; disease phenotype; enzyme activity; epigenetic regulation; in vivo; insight; knock-down; liver injury; mouse model; novel; promoter; protein function; targeted treatment; transcriptome sequencing; upstream kinase; 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine; Affect; Alcohol-Induced Disorders; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Animal Feed; Animals; Apoptosis; Arginine; Binding; Cell Cycle; Cell Proliferation; Cell Survival; Cessation of life; ChIP-seq; Cirrhosis; Clinical; Data; Defect; Disease; Disease Progression; Enzymes; Epigenetic Process; Equilibrium; Fibrosis; Future; Gene Expression; Genes; Genetic; Glycine decarboxylase; Goals; Hepatocyte; Histones; In Vitro; Individual; Inflammation; Injections; Knock-out; Knockout Mice; Lipids; Liver; Liver diseases; LoxP-flanked allele; Mass Spectrum Analysis; Measures; Mediating; Methylation; Modification; Mus; Nature; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Post-Translational Protein Processing; Predisposition; Proliferating; Protein Dephosphorylation; Protein-Arginine N-Methyltransferase; Proteins; Regulation; Role; Sampling; Serum; Severity of illness; Specificity; System; Testing; Therapeutic; alcohol exposure; alcohol involvement; alcohol prevention; alcohol sensitivity; demethylation; disease phenotype; enzyme activity; epigenetic regulation; in vivo; insight; knock-down; liver injury; mouse model; novel; promoter; protein function; targeted treatment; transcriptome sequencing; upstream kinase

PROJECT SUMMARY Alcoholic liver disease is a major clinical problem with unknown susceptibility factors. It displays marked variability in disease phenotype. Only about 15% of heavy drinkers develop disease while 85% appear to be protected, suggesting that there are mechanisms of adaptation to alcohol in majority of individuals. Arginine methylation is a common posttranslational modification (PTM) that regulates hundreds of proteins directly and many more via histone arginine methylation (epigenetic regulation). Protein arginine methyltransferase 1 (PRMT1) is the main enzyme responsible for about 90% of cellular arginine methylation. JMJD6 is the only known arginine demethylase Preliminary data indicate that patients with alcoholic liver disease have extremely low levels of PRMT1 protein compared other patient groups suggesting that PRMT1 might be involved in disease progression of these patients. Using hepatocyte specific knockout mouse model, we found that PRMT1 knockout in alcohol fed mice results in dramatic increase in hepatocyte death, steatosis, inflammation and fibrosis; and increased serum ALT levels suggesting that PRMT1 is protective against alcohol induced liver injury. This function of PRMT1 is specific to alcohol, and preliminary data suggests that it is mediated by alcohol induced dephosphorylation of PRMT1. We thus hypothesize that alcohol induced changes in PRMT1 activity are necessary for liver adaptation to alcohol. This project will specifically examine this hypothesis with the following specific aims: Specific Aim 1. To study the mechanism of PRMT1 mediated alcohol sensitivity. We will study non- histone targets and promoter arginine methylation and define the major pathways. Specific Aim 2. To define the role of PRMT1 phosphorylation in protection from alcohol induced liver injury. We hypothesize that dephosphorylated form is particularly protective from alcohol induced injury. Inhibiting the upstream kinase in this case is a promising future therapeutic strategy. Specific Aim 3. To define the role of arginine demethylation enzyme JMJD6 in susceptibility to alcohol induced liver injury. JMJD6 is another promising target. JMJD6 inhibition reverts the phenotype of PRMT1 knockout mice. We will study the mechanism of this regulation. Results of the proposed project will provide novel insights into the nature of the arginine methylation defects in alcoholic liver disease. It should determine whether PRMT1 and JMJD6 are essential regulators of the hepatocyte adaptation to alcohol and identify the primary targets. The project will set the stage for further studies to understand the alcohol susceptibility in patients and explore the potential targets for therapy. The ultimate goal is to use this information to develop clinical strategies to treat alcohol associated liver disease.

项目摘要 酒精性肝病是未知易感因素的主要临床问题。它显示标记 疾病表型的变异性。只有大约15％的重量饮酒者患疾病，而85％的人似乎是 受到保护，表明大多数个体有适应酒精的机制。精氨酸 甲基化是一种常见的翻译后修饰（PTM），可直接调节数百种蛋白质，并且 更多通过组蛋白精氨酸甲基化（表观遗传调节）。蛋白精氨酸甲基转移酶1 （PRMT1）是负责约90％细胞精氨酸甲基化的主要酶。 JMJD6是唯一的 已知的精氨酸脱甲基酶 初步数据表明，酒精性肝病患者的PRMT1蛋白水平极低 比较其他患者群体，表明PRMT1可能参与了这些疾病的进展 患者。使用肝细胞特异性敲除鼠标模型，我们发现酒精喂养的小鼠中的PRMT1敲除 导致肝细胞死亡，脂肪变性，炎症和纤维化的急剧增加。并增加血清 ALT水平表明PRMT1可防止酒精诱导的肝损伤。 PRMT1的此功能是 特定于酒精，初步数据表明，它是由酒精诱导的去磷酸化介导的 PRMT1。因此，我们假设酒精引起的PRMT1活性的变化对于肝脏是必需的 适应酒精。该项目将以以下特定目的专门研究该假设： 具体目的1。研究PRMT​​1介导的酒精敏感性的机制。我们将研究非 组蛋白靶标和启动子精氨酸甲基化并定义主要途径。特定目标2。定义 PRMT1磷酸化在保护饮酒诱导肝损伤中的作用。我们假设这一点 去磷酸化的形式特别保护酒精诱导的损伤。抑制上游激酶 这种情况是一种有希望的未来治疗策略。特定目的3。定义精氨酸的作用 脱甲基化酶JMJD6对酒精诱发肝损伤的敏感性。 JMJD6是另一个 有希望的目标。 JMJD6抑制作用恢复了PRMT1敲除小鼠的表型。我们将研究 该法规的机制。 拟议项目的结果将提供有关精氨酸甲基化缺陷性质的新见解 酒精性肝病。它应该确定PRMT1和JMJD6是否是必不可少的调节剂 肝细胞适应酒精并确定主要靶标。该项目将为进一步奠定舞台 研究以了解患者的酒精敏感性并探索治疗的潜在靶标。这 最终目标是使用这些信息来制定临床策略来治疗酒精相关的肝病。