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）：由于饮酒过量而引起的酒精性肝病（ALD）是全球领先的慢性肝脏疾病之一。 ALD包括一系列肝脏疾病，从简单脂肪肝脏到酒精性肝炎，肝硬化和肝Faiure。当前对严重ALD（例如酒精性肝炎）的治疗受到限制，并且缺乏长期疗效。因此，迫切需要开发新的治疗剂来阻止或延迟最终的器官故障并降低巨大的医疗费用。 ALD中的主要病理特征之一是肝内存在延长和低度炎症反应。升高的内毒素水平激活肝巨噬细胞（kupffer细胞）会产生氧化应激，并产生多种促炎性细胞因子，从而导致肝细胞的凋亡增加，过多产生细胞外基质基质蛋白的产生，并产生纤维化。因此，在存在慢性乙醇的情况下，巨噬细胞与肝细胞之间的复杂相互作用可能会促进未解决的炎症。更好地理解如何限制肝脏中的炎症和凋亡将揭示出有效的治疗和预防ALD。作为在肝细胞中高度表达的关键昼夜节律蛋白，BMAL1调节昼夜节律基因的振荡以及参与脂质和葡萄糖代谢的基因。我们发现BMAL1缺乏加剧了小鼠脂多糖（LPS）或急性酒精中毒引起的肝损伤。 BMAL1 - / - 小鼠中肝损伤的严重程度与炎症和细胞凋亡增加有关，表明需要正常的BMAL1蛋白表达或功能来保护肝细胞免受凋亡的凋亡，并抑制对肝损伤治疗的响应。基于这些新的初步数据，我们假设BMAL1通过促进肝细胞存活并减轻慢性肝炎症在酒精肝病的发展中起着至关重要的作用。我们将以两个具体目标来检验该假设。在AIM 1中，我们将确定肝细胞特异性BMAL1缺乏症是否足以增强酒精喂养过程中的肝脏炎症和损伤。在AIM 2中，我们将通过激活促凋亡转录因子FOXO1来确定BMAL1缺乏症是否使肝细胞对乙醇诱导的凋亡敏感。我们将确定抑制FOXO1对BMAL1 - / - 敲除小鼠肝损伤的影响。成功完成申请将产生有关酒精引起的肝损伤的新见解，并确定治疗ALD的新策略。