Nrf2 as a Master Regulator in Liver Disease Prevention and Therapy

Nrf2 作为肝病预防和治疗的主调节因子

基本信息

批准号：
7654392
负责人：
CURTIS DEAN KLAASSEN
金额：
$ 36.36万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7654392
关键词：
Active Sites Animal Model Anions Anti-Inflammatory Agents Anti-inflammatory Antioxidants Applications Grants Attention Basic Science Biliary Binding Binding Sites Cell Line Cell Nucleus Cells Chemicals Chimeric Proteins Chinese People Chromatin Chromosomes, Human, Pair 10 Cirrhosis Collaborations Cysteine Cytoprotection Cytosol Data Development Diet Disease Disease Outcome Disease susceptibility Drug Delivery Systems Elements Ensure Epigenetic Process Etiology Excretory function Exhibits Fatty acid glycerol esters Foundations Functional disorder Gene Expression Gene Mutation Gene Targeting Genes Genetic Models Genetic Transcription Genome Glutathione Goals Green Fluorescent Proteins Hepatic Hepatocyte Hepatotoxicity Histone H3 Homologous Gene Human Image Immune Immunomodulators Inflammation Inflammatory Inflammatory Response Injury Interferon Type II Intervention Knock-out Knockout Mice Lead Lipid Peroxidation Liver Liver Failure Liver Fibrosis Liver diseases Lysine Malnutrition Maps Mediating Medical Messenger RNA Metabolic Biotransformation Modeling Molecular Monitor Mus Nuclear Nuclear Translocation Oleanolic Acid Oxidative Stress Pathogenesis Pharmaceutical Preparations Pharmacology and Toxicology Phosphoric Monoester Hydrolases Play Poison Preparation Prevention Prevention strategy Prevention therapy Proteins Public Health Regulation Resolution Role Screening procedure Signal Transduction Solid Specificity Steatohepatitis T-Lymphocyte Techniques Testing Therapeutic Therapeutic Intervention Time Toxic effect Tumor Suppressor Genes Ubiquitination Up-Regulation Wound Healing adapter protein analog base cell type chromatin immunoprecipitation cytokine disorder prevention drug development experience feeding hepatotoxin high throughput screening innovation liver pharmacology mouse genome mouse model multidisciplinary new therapeutic target nonalcoholic steatohepatitis novel nuclear factor-erythroid 2 prevent public health relevance research study response small molecule libraries tensin therapeutic target tool toxicant transcription factor

项目摘要

DESCRIPTION (provided by applicant): Current therapeutic interventions for treating liver diseases are very limited; identification of a therapeutic target is a prerequisite for developing new drugs to treat liver diseases. Oxidative stress and inflammation play key roles in the pathogenesis of liver diseases. Nuclear factor 2-related factor 2 (Nrf2), a transcription factor expressed in both hepatocytes and immune cells, is a key factor in anti-oxidative and anti-inflammatory responses. In quiescent hepatocytes, Nrf2 is sequestered in cytosol by kelch-like ECH-associated protein 1 (Keap1); in Keap1-knockdown mice, nuclear translocation of Nrf2 increases, resulting in activation of Nrf2 target genes. The importance of Nrf2 in cytoprotection is recognized. Nevertheless, the role of Nrf2 in liver pathophysiology has just recently gained attention. Our long-term goal is to identify a novel drug target and develop a therapeutic/preventive strategy for liver diseases. The objective of this R01 grant proposal is to investigate in-depth the role of Nrf2 in protecting against liver pathophysiology and understand its underlying molecular mechanisms. Based upon our strong preliminary data, our central hypothesis is that Nrf2 is a master regulator of liver protection through its multifaceted roles in biotransformation/disposition, antioxidation, tissue- repair, and anti-inflammation in multiple cell types in liver. Aim 1 will identify direct targets of Nrf2 regulation using ChIP-Sequencing and determine Nrf2-dependent mRNA induction in the Keap1-knockdown mouse. Aim 2 will test the hypothesis that Nrf2 activation protects against chemical, dietary, and genetic models of liver disease. We will use 3 genetic models of mice with differential Nrf2 activity, namely Nrf2-null, wild-type, and Nrf2-enhanced mice, to test liver disease susceptibility in 13 different models. Aim 3 will develop novel and specific Nrf2 activator lead candidates by high throughput screening in collaboration with the Office of Therapeutics, Discovery, and Development. Our proposed study is novel, because it utilizes 3 mouse lines with different Nrf2 activities to investigate the opposing effects of Nrf2 deficiency and Nrf2 activation on liver diseases induced via diverse mechanisms of toxicity. This proposal utilizes innovative techniques including ChIP-sequencing, multiplex mRNA analysis, and nuclear translocation high throughput screening in testing the 3 aims. Our proposed study is significant, because results from our experiments will provide solid evidence regarding the importance of Nrf2 deficiency and Nrf2 activation in liver pathophysiology and its underlying molecular mechanisms, setting the scientific foundation for developing Nrf2 activators as novel drugs to treat/prevent various liver diseases, such as chemical-induced liver injury, inflammatory liver diseases, steatohepatitis, and liver fibrosis/cirrhosis. PUBLIC HEALTH RELEVANCE: Liver disease is a common ailment, however in contrast to most other diseases, there are very few drugs for liver failure. We hypothesize that Nrf2, an essential transcription factor, is a drug target that can be used to prevent and treat a wide-range of liver ailments. This study will determine whether this drug target will be effective against a wide-spectrum of animal models of liver disease.

描述（由申请人提供）：治疗肝病的当前治疗干预措施非常有限；鉴定治疗靶标是开发新药物治疗肝病的先决条件。氧化应激和炎症在肝病的发病机理中起关键作用。核因子2相关因子2（NRF2）是在肝细胞和免疫细胞中表达的转录因子，是抗氧化和抗炎反应的关键因素。在静止的肝细胞中，NRF2通过Kelch样ECH相关蛋白1（KEAP1）在细胞质中隔离。在KEAP1-KNOCKDOWN小鼠中，NRF2的核转运增加，导致NRF2靶基因的激活。 NRF2在细胞保护中的重要性已确认。然而，NRF2在肝病生理学中的作用最近引起了人们的关注。我们的长期目标是确定一个新的药物靶标，并针对肝脏疾病制定治疗/预防策略。该R01赠款提案的目的是深入研究NRF2在保护肝病生理学中的作用并了解其潜在的分子机制。基于我们强大的初步数据，我们的中心假设是NRF2是通过其在生物转化/处置，抗氧化，组织修复和抗炎中多种细胞中多种细胞类型中的多方面保护作用的主要调节剂。 AIM 1将使用芯片序列确定NRF2调控的直接靶标，并确定KEAP1敲低小鼠中NRF2依赖性mRNA诱导。 AIM 2将检验以下假设：NRF2激活可以预防肝病的化学，饮食和遗传模型。我们将使用3种具有差异NRF2活性的小鼠的遗传模型，即NRF2-NULL，野生型和NRF2增强小鼠，以测试13种不同模型的肝病敏感性。 AIM 3将通过与治疗，发现和开发办公室合作进行高吞吐量筛查来开发新颖和特定的NRF2激活量候选者。我们提出的研究是新颖的，因为它利用3条具有不同NRF2活性的小鼠系来研究NRF2缺乏症和NRF2激活对通过毒性的多种机制诱导的肝脏疾病的相反作用。该建议利用创新技术，包括芯片测序，多重mRNA分析和核易位高吞吐量筛选，以测试3个目标。 Our proposed study is significant, because results from our experiments will provide solid evidence regarding the importance of Nrf2 deficiency and Nrf2 activation in liver pathophysiology and its underlying molecular mechanisms, setting the scientific foundation for developing Nrf2 activators as novel drugs to treat/prevent various liver diseases, such as chemical-induced liver injury, inflammatory liver diseases, steatohepatitis, and liver纤维化/肝硬化。公共卫生相关性：肝病是一种常见的疾病，但是与大多数其他疾病相比，肝脏衰竭的药物很少。我们假设NRF2是一种必不可少的转录因子，是一个可用于预防和治疗大范围肝病的药物靶标。这项研究将确定该药物靶标是否对肝病的动物模型有效。