Proteomic profiling of NASH: disease mechanisms and novel treatment

NASH 的蛋白质组学分析：疾病机制和新的治疗方法

基本信息

批准号：
7488900
负责人：
DENNIS PETERSEN
金额：
$ 30.71万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7488900
关键词：
4 hydroxynonenal Adult Adverse effects Affect Aldehydes Animal Model Animals Antibodies Attenuated Biochemical Cell Death Cells Cessation of life Child Cirrhosis Classification Complex Condition Data Diet Disease Event Fatty Liver Fatty acid glycerol esters Fibrosis GRP78 gene Goals Hepatic Hepatocyte Histopathology Homeostasis In Vitro Inflammation Inflammatory Ingestion Injury Insulin Resistance Investigation Link Lipid Peroxidation Lipids Liver diseases Lobular Long-Chain-Acyl-CoA Dehydrogenase Mass Spectrum Analysis Metabolic Metabolic Pathway Mitochondria Modification Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Pathogenesis Play Population Post-Translational Protein Processing Prevalence Production Property Proteins Proteome Proteomics Range Reactive Oxygen Species Research Personnel Resolution Role Series Staging Stress Supplementation Taurine Testing Therapeutic Triglycerides Tumor Necrosis Factor-alpha United States Work adiponectin base biological adaptation to stress cofactor cytokine cytotoxicity design efficacy evaluation fatty acid oxidation feeding human TNF protein insight insulin sensitivity mouse model non-alcoholic fatty liver nonalcoholic steatohepatitis novel oxidation programs research study response restoration

项目摘要

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is a multifactorial clinicopathologic condition characterized by marked lipid accumulation in hepatocytes. The prevalence ranges from 10-24% across a spectrum of populations with upwards to 58% of obese adults and 53% of obese children affected by this disorder. The mechanisms underlying the transition of this disease to the more advanced stage, (NASH), characterized by hepatosteatosis, hepatocyte death and fibrosis remain to be elucidated although oxidative stress is proposed to play a central role in this progression. Oxidative stress is characterized by the production of reactive oxygen species (ROS) which initiate lipid peroxidation giving rise to bioactive aldehydic products of lipid peroxidation including 4-hydroxy-2-nonenal (4-HNE) and 4-oxononenal (4-ONE). It is our working hypothesis that specific protein modifications by 4-HNE and 4-ONE play important roles in the pathogenesis of NASH. This hypothesis will be tested by systematic experiments proposed in three specific aims using a mouse model of dietary-induced fatty liver. Experiments in Aim 1 will establish mechanistic relationships of documented biochemical and metabolic hallmarks of NAFLD and NASH with hepatic oxidative stress to delineate the ability of 4-HNE and 4-ONE to orchestrate the "second hit". Parameters to be characterized which emerge during the progression of NAFLD and NASH include hepatic histopathology, insulin sensitivity, dysregulation of lipid homoeostasis, increased production of TNF-a, decreases in adiponectin, the overproduction of proinflammatory cytokines as well as inflammation and fibrosis. Experiments in Aim 2 will identify hepatic proteins modified by 4-HNE and 4-ONE with the goal of identifying mechanistic links with initiation and progression of NASH. Experiments are proposed using the candidate proteins, long-chain acyl CoA dehydrogenase and the ER stress modulator GRP78 to evaluate the functional consequences of protein modification by 4-HNE and 4-ONE produced in association with NASH. Novel studies in Aim 3 will employ proteomic approaches to evaluate the hepatoprotective mechanisms of taurine supplementation in arresting NAFLD and NASH by restoration of ER stress response and protection against TNF-alpha-induced cell death. These proposed experiments will provide new insight into the pathomechanisms of NAFLD and potential therapeutic approaches to the treatment of this liver disease.

描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）是一种多因素临床病理病症，其特征是肝细胞中明显的脂质积累。在各种人群中，患病率为 10-24%，其中高达 58% 的肥胖成人和 53% 的肥胖儿童受到这种疾病的影响。这种疾病向以肝脂肪变性、肝细胞死亡和纤维化为特征的更晚期（NASH）转变的机制仍有待阐明，尽管氧化应激被认为在这一进展中发挥着核心作用。氧化应激的特点是产生活性氧 (ROS)，引发脂质过氧化，产生脂质过氧化的生物活性醛产物，包括 4-羟基-2-壬烯醛 (4-HNE) 和 4-氧壬烯醛 (4-ONE)。我们的工作假设是 4-HNE 和 4-ONE 的特定蛋白质修饰在 NASH 的发病机制中发挥重要作用。这一假设将通过系统实验进行检验，该实验针对三个特定目标，使用饮食诱发脂肪肝的小鼠模型。目标 1 中的实验将建立 NAFLD 和 NASH 的生化和代谢特征与肝脏氧化应激的机械关系，以描述 4-HNE 和 4-ONE 协调“第二次打击”的能力。 NAFLD 和 NASH 进展过程中出现的待表征参数包括肝组织病理学、胰岛素敏感性、脂质稳态失调、TNF-a 产生增加、脂联素减少、促炎细胞因子过度产生以及炎症和纤维化。目标 2 中的实验将鉴定经 4-HNE 和 4-ONE 修饰的肝蛋白，目的是确定与 NASH 发生和进展的机制联系。建议使用候选蛋白质、长链酰基 CoA 脱氢酶和 ER 应激调节剂 GRP78 进行实验，以评估与 NASH 相关的 4-HNE 和 4-ONE 产生的蛋白质修饰的功能后果。 Aim 3 的新研究将采用蛋白质组学方法来评估补充牛磺酸通过恢复内质网应激反应和防止 TNF-α 诱导的细胞死亡来阻止 NAFLD 和 NASH 的保肝机制。这些拟议的实验将为 NAFLD 的病理机制和治疗这种肝病的潜在治疗方法提供新的见解。