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BMAL1: A Novel Regulator For Inflammatory Liver Injury

BMAL1：炎症性肝损伤的新型调节剂

基本信息

批准号：
8771901
负责人：
Lei Yin
金额：
$ 18.43万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771901
关键词：
Acute Affect Alcohol consumption Alcoholic Fatty Liver Alcoholic Hepatitis Alcoholic Intoxication Alcoholic Liver Diseases Alcohols Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Attention BMAL1 protein Biochemical Genetics Biological Process Brain Cells Cessation of life Chronic Circadian Rhythms Clock protein Collagen Complex Cues Data Development Diet Dominant-Negative Mutation Endotoxins Energy Metabolism Ethanol Ethanol Metabolism Extracellular Matrix Proteins Fatty Liver Fatty acid glycerol esters Fibrosis Functional disorder Genes Genetic Goals Hepatic Hepatocyte In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Injury to Liver Knockout Mice Kupffer Cells Life Light Link Lipopolysaccharides Liver Liver Cirrhosis Liver Failure Liver diseases Mediating Medical Molecular Molecular Target Mus Muscle Neutrophil Infiltration Nuclear Organ failure Oxidative Stress Pathogenesis Patients Physiological Play Positioning Attribute Post-Translational Protein Processing Prevention Production Proteins Public Health Regulation Role Severities Staging Testing Therapeutic Therapeutic Intervention United States alcohol response base cell injury chronic alcohol ingestion chronic liver disease circadian pacemaker cost cytokine effective therapy feeding glucose metabolism human ARNT protein insight lipid metabolism liver inflammation liver injury liver transplantation macrophage mortality mouse model new therapeutic target novel novel therapeutics pro-apoptotic protein problem drinker protein expression protein function public health relevance response response to injury small hairpin RNA tool transcription factor treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): Caused by excessive alcohol drinking, alcoholic liver disease (ALD) is one of the leading chronic liver diseases worldwide. ALD includes a spectrum of liver disorders ranging from simple fatty liver to alcoholic hepatitis, cirrhosis, and liver faiure. Current treatment for severe ALD such as alcoholic hepatitis is limited and lacks long-term efficacy. Therefore, there is an urgent need for developing new therapeutics to block or delay the eventual organ failure and reduce the huge medical costs. One of the main pathological features in ALD is the presence of prolonged and low-grade inflammatory response within liver. Activation of hepatic macrophages (Kupffer cells) by elevated endotoxin levels generates oxidative stress and produces a variety of pro-inflammatory cytokines, which result in increased apoptosis of hepatocytes, excessive production of extracellular matrix proteins, and fibrosis. Thus, a complex interaction between macrophages and hepatocytes might promote unsolved inflammation in the presence of chronic ethanol consumption. A better understanding of how to restrain inflammation and apoptosis in the liver will shed light on developing effective treatment and prevention of ALD. As a key circadian clock protein, highly expressed in hepatocytes, BMAL1 regulates oscillations of circadian genes as well as genes involved in lipid and glucose metabolism. We discovered that Bmal1 deficiency exacerbates liver injury induced by either lipopolysaccharide (LPS) or acute alcohol intoxication in mice. The severity of liver injury in Bmal1-/- mice is associated with increased inflammation and cell apoptosis, suggesting that normal BMAL1 protein expression or function is required to protect hepatocytes from apoptosis and suppress inflammation in response to liver injury treatment. Based on these novel preliminary data, we hypothesize that BMAL1 plays a critical role during the progression of alcohol liver disease by promoting hepatocyte survival and alleviating chronic hepatic inflammation. We will test the hypothesis in two specific aims. In Aim 1, we will determine whether hepatocyte-specific Bmal1 deficiency is sufficient to enhance liver inflammation and injury during alcohol feeding. In Aim 2, we will determine whether BMAL1 deficiency sensitizes hepatocyte to ethanol-induced apoptosis via activating pro-apoptotic transcription factor FOXO1. We will determine the effects of inhibition of FOXO1 on liver injury in Bmal1-/- knockout mice. Successful completion of the application will yield new insights on alcohol-induced liver injury and identify new strategies for the treatment of ALD.

描述（由申请人提供）：酒精性肝病（ALD）是由过量饮酒引起的，是全球主要的慢性肝病之一。ALD包括一系列肝脏疾病，从单纯性脂肪肝到酒精性肝炎、肝硬化和肝衰竭。目前对酒精性肝炎等严重ALD的治疗是有限的，缺乏长期疗效。因此，迫切需要开发新的治疗方法来阻断或延迟最终的器官衰竭并降低巨大的医疗成本。ALD的主要病理特征之一是肝脏内存在长期和低度炎症反应。升高的内毒素水平激活肝巨噬细胞（枯否细胞）产生氧化应激并产生多种促炎细胞因子，导致肝细胞凋亡增加、细胞外基质蛋白过度产生和纤维化。因此，巨噬细胞和肝细胞之间的复杂相互作用可能会促进慢性乙醇消耗存在下未解决的炎症。更好地了解如何抑制肝脏中的炎症和凋亡将有助于开发有效的治疗和预防ALD。作为一种重要的生物钟蛋白，BMAL 1在肝细胞中高度表达，调节昼夜节律基因以及参与脂质和葡萄糖代谢的基因的振荡。我们发现Bmal 1缺陷会加重由脂多糖（LPS）或急性酒精中毒引起的小鼠肝损伤。Bmal 1-/-小鼠肝损伤的严重程度与炎症和细胞凋亡的增加相关，表明正常的BMAL 1蛋白表达或功能是保护肝细胞免于凋亡和抑制炎症对肝损伤治疗的反应所必需的。基于这些新的初步数据，我们假设BMAL 1通过促进肝细胞存活和减轻慢性肝脏炎症在酒精性肝病的进展过程中起着关键作用。我们将在两个具体目标中检验这一假设。在目标1中，我们将确定肝细胞特异性Bmal 1缺陷是否足以增强酒精喂养期间的肝脏炎症和损伤。在目标2中，我们将确定BMAL 1缺陷是否通过激活促凋亡转录因子FOXO 1使肝细胞对乙醇诱导的凋亡敏感。我们将确定抑制FOXO 1对Bmal 1-/-敲除小鼠肝损伤的影响。该申请的成功完成将对酒精性肝损伤产生新的见解，并确定治疗ALD的新策略。