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：
7323064
负责人：
DENNIS PETERSEN
金额：
$ 31.35万
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/7323064
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）：非酒精性脂肪肝疾病（NAFLD）是一种多因素临床病理状况，其特征是肝细胞中脂质的显着积累。在一系列人群中，患病率的范围为10-24％，肥胖成年人中有58％，53％受这种疾病影响的肥胖儿童。该疾病向更高级阶段过渡的基础机制，即（NASH），其特征是肝脏，肝细胞死亡和纤维化的特征，尽管提出氧化应激在此进展中起着核心作用，但仍尚待阐明。氧化应激的特征在于产生活性氧（ROS），这些氧气启动脂质过氧化，从而导致脂质过氧化的生物活性醛产物，包括4-羟基-2-硝基（4-HNE）和4-氧onenenal和4-氧合烯烯（4-对）。正是我们的工作假设是，特定的蛋白质通过4-HNE修饰，而4个则在NASH的发病机理中起重要作用。该假设将通过使用饮食诱导的脂肪肝的小鼠模型在三个特定目的中提出的系统实验进行检验。 AIM 1中的实验将建立NAFLD和NASH的生化和代谢标志的机械关系，并具有肝氧化应激，以描绘4-HNE和4-One协调“第二击”的能力。要表征的参数在NAFLD和NASH的进展过程中出现的参数包括肝组织病理学，胰岛素敏感性，脂质同源性的失调，TNF-A的产生增加，脂联素的产生，降低脂肪素，促症细胞因子的过度产生以及炎症和纤维化和纤维化和纤维化的过度产生。 AIM 2中的实验将识别由4-HNE修饰的肝蛋白和4-ONE修饰的肝蛋白，目的是识别机械联系，并与NASH的起始和进展。提出了使用候选蛋白，长链酰基CoA脱氢酶和ER应力调节剂GRP78提出的实验，以评估4-HNE蛋白质修饰的功能后果，而与NASH相关的4-HE产生。 AIM 3中的新研究将采用蛋白质组学方法来评估牛磺酸补充的肝保护机制，以通过恢复AR应力反应并保护TNF-Alpha诱导的细胞死亡来阻止NAFLD和NASH。这些提出的实验将为NAFLD的病理机理以及治疗这种肝病的潜在治疗方法提供新的见解。