Angiotensin II and NADPH Oxidase in Hepatic Fibrosis

血管紧张素 II 和 NADPH 氧化酶在肝纤维化中的作用

基本信息

批准号：
7491160
负责人：
DAVID A. BRENNER
金额：
$ 32.3万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7491160
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Agonist Alleles Angiotensin II Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Apoptosis Biological Markers Blood Vessels Cell Proliferation Cells Chronic Cirrhosis Collagen Complex Critical Pathways Data Development Endocannabinoids Enzymes Experimental Animal Model Experimental Models Extracellular Matrix Extracellular Matrix Proteins Fibrosis Gene Expression Generations Genes Genetic Hepatic Hepatic Fibrogenesis Hepatic Stellate Cell Human Inflammation Inflammatory Intervention Knock-in Mouse Knockout Mice Laboratories Lead Leptin Ligation Liver Liver Failure Liver Fibrosis Liver diseases Mediating Mediator of activation protein Modeling Monitor Mus NADP NADPH Oxidase Oxidases Patients Pharmaceutical Preparations Physiological Platelet-Derived Growth Factor Portal Hypertension Primary carcinoma of the liver cells Production Protein Biosynthesis Reactive Oxygen Species Relative (related person)Renin Reporter Research Personnel Role Series Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes System Toxin Transforming Growth Factor beta base bile duct cytokine fibrogenesis human AKAP13 protein in vivo inhibitor/antagonist insight novel receptor response

项目摘要

DESCRIPTION (provided by applicant): Liver fibrosis, the accumulation of extracellular matrix (ECM) proteins, occurs in most types of chronic liver diseases. Liver fibrosis progresses to cirrhosis with subsequent portal hypertension, hepatic failure, and hepatocellular carcinoma, Activated hepatic stellate cells (HSCs) are the major ECM producing cell in the fibrogenic liver and key fibrogenic signals have been identified, including transforming drug factor beta (TGFbeta), reactive oxygen species (ROS), and Ang II. We have demonstrated that the key signaling pathway activated by Ang II in activated HSC is the endogenous generation of ROS by NADPH oxidase and that the downstream effects module HSC proliferation, production of ECM proteins, and synthesis of inflammatory cytokines. Thus we have begun to elucidate the mechanistic relationship between inflammation, Ang II, reactive oxygen species, and hepatic fibrosis. We wish to pursue four specific aims to further characterize the role of Ang II in hepatic fibrosis and the downstream activation of NADPH oxidase. The underlying hypotheses that serve as the basis for this proposal are the following: 1.The renin-angiotensinogen system is a critical pathway in hepatic fibrosis. 2. The major mediator of the effects of Ang II including changes in gene expression is the activation of NADPH oxidase. 3. Other fibrogenic factors also induce NADPH oxidase, so that this enzyme becomes the critical mediator of the generation of reactive oxygen species and subsequent induction of fibrogenesis. 4. New insights into the mechanisms by which Ang II and NADPH oxidase mediate hepatic fibrogenesis will lead to the development of novel therapies for patients with fibrotic liver diseases. The specific aims of the proposal are: 1. To define the components of the NADPH oxidase complex in hepatic stellic cells. 2. To assess the effect of inhibiting Ang II on hepatic fibrosis and hepatic stellate cell apoptosis. 3. To assess the effect of titrating the angiotensinogen gene in models of hepatic fibrosis. 4. To determine if other mediators of hepatic fibrosis in addition to Ang II activate NADPH oxidase.

描述（由申请人提供）：肝纤维化，即细胞外基质（ECM）蛋白的积累，发生在大多数类型的慢性肝病中。肝纤维化进展为肝硬化，随后出现门静脉高压、肝功能衰竭和肝细胞癌。活化的肝星状细胞 (HSC) 是纤维化肝脏中主要的 ECM 产生细胞，并且已经确定了关键的纤维化信号，包括转化药物因子 β (TGFbeta) 、活性氧 (ROS) 和 Ang II。我们已经证明，Ang II 在活化的 HSC 中激活的关键信号通路是 NADPH 氧化酶内源性产生 ROS，并且下游影响模块 HSC 增殖、ECM 蛋白的产生和炎症细胞因子的合成。因此，我们已经开始阐明炎症、血管紧张素II、活性氧和肝纤维化之间的机制关系。我们希望实现四个具体目标，以进一步表征 Ang II 在肝纤维化和 NADPH 氧化酶下游激活中的作用。作为该提案基础的基本假设如下： 1.肾素-血管紧张素原系统是肝纤维化的关键通路。 2. Ang II 影响（包括基因表达变化）的主要调节因素是 NADPH 氧化酶的激活。 3.其他纤维形成因子也诱导NADPH氧化酶，因此该酶成为活性氧生成和随后诱导纤维形成的关键介质。 4. 对Ang II和NADPH氧化酶介导肝纤维化机制的新见解将导致纤维化肝病患者新疗法的开发。该提案的具体目标是： 1. 明确肝星状细胞中NADPH氧化酶复合物的成分。 2.评估抑制Ang II对肝纤维化和肝星状细胞凋亡的影响。 3. 评估肝纤维化模型中血管紧张素原基因滴定的效果。 4. 确定除Ang II之外的其他肝纤维化介质是否激活NADPH氧化酶。