Oxidative Stress and Hepatocellular Carcinoma

氧化应激与肝细胞癌

基本信息

批准号：
7679644
负责人：
Ting-Ting Huang
金额：
$ 26.6万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
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：
2007-09-21 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7679644
关键词：
Accounting Adult Affect Animals Antioxidants Biological Markers Calcium Cell Line Cells China Chronic Cirrhosis Clinical Research Country Development Genes Genetic Goals Hand Hemochromatosis Hepatitis B Hepatitis B Virus Hepatitis C Hepatocarcinogenesis Hepatocyte Homeostasis Human In Vitro Infection Injury Investigation Italy Japan Left Life Liver Liver diseases Liver neoplasms Long-Term Effects Longitudinal Studies Malignant Neoplasms Malignant neoplasm of liver Mediating Metabolism Modeling Modification Molecular Molecular Target Mus Mutant Strains Mice Mutation Operative Surgical Procedures Oxidation-Reduction Oxidative Stress Patients Play Primary carcinoma of the liver cells Probability Procedures Production Protein C Inhibitor Proteins Proteomics Risk Factors Role Signaling Molecule Superoxide Dismutase Surveys System Taiwan Time Transgenic Mice Transgenic Organisms Treatment outcome Tumor Tissue United States base biological adaptation to stress citrate carrier comparative congenic copper zinc superoxide dismutase driving force free radical oxygen in vivo mouse model mutant non-alcoholic fatty liver nonalcoholic steatohepatitis oxidation oxidative damage problem drinker tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): This proposal is based on the hypothesis that oxidative stress and injury is a common and major driving force of hepatocellular carcinoma (HCC) in chronic liver diseases and that decreased antioxidant capacity increases the probability of HCC development in patients with chronic liver diseases. Therefore, the long term objectives of this proposal are to determine the mechanism underling oxidative stress-mediated HCC development from hepatitis C (HCV) infection and to identify risk factors and oxidative stress-mediated biomarkers associated with the progression of HCC. Several clinical studies showed a causal relationship between low levels of superoxide dismutase (SOD) and the development of HCC; several mouse models generated to recapitulate HCC development were shown to have elevated levels of oxidative damage; and mutant mice with genetic defects in oxygen free radical metabolism develop HCC after a long incubation time. Collectively, these studies suggest that oxidative stress may play a direct and important role in the development of HCC in chronic liver diseases. We will focus our studies on the interplay between HCV-mediated HCC development, oxidative stress, and SOD deficiency in this proposal. Three Specific Aims are proposed to determine the relationship between HCV infection, ROS production, calcium homeostasis, and hepatocarcinogenesis, to determine the role of SOD in the development of HCV-mediated hepatocarcinogenesis, and to identify molecular targets common to chronic HCV infection and SOD deficiency by comparative proteomic analyses. In vitro and in vivo studies using established human liver cell line, primary human hepatocytes, HCV transgenic mice, and CuZnSOD deficient mice will be carried out to determine the effects of HCV proteins on ROS production, calcium homeostasis, and the activation of redox-sensitive signaling molecules. A genetic approach will be used to reduce SOD levels in HCV transgenic mice to modulate the course of HCC development. In addition, different proteomic tools and procedures will be implemented to identify molecules that are vulnerable to oxidative modification in HCV transgenic and CuZnSOD deficient mice.

描述（由申请人提供）：该提案基于以下假设：氧化应激和损伤是慢性肝病中肝细胞癌（HCC）的常见且主要的驱动力，而抗氧化能力降低会增加慢性肝脏疾病患者HCC发育的可能性。因此，该提案的长期目标是确定丙型肝炎（HCV）感染的氧化应激介导的HCC发育的机制，并确定与HCC进展相关的危险因素和氧化应激介导的生物标志物。几项临床研究表明，低水平的超氧化物歧化酶（SOD）与HCC的发展之间存在因果关系。显示出用于概括HCC发育的几种小鼠模型的氧化损伤水平升高。在长时间孵化后，氧自由基代谢中具有遗传缺陷的突变小鼠会发展出HCC。总的来说，这些研究表明，氧化应激可能在慢性肝病中HCC的发展中起着直接而重要的作用。我们将把研究重点放在该提案中HCV介导的HCC发育，氧化应激和SOD缺乏之间的相互作用上。提出了三个具体目的来确定HCV感染，ROS产生，钙稳态和肝癌发生之间的关系，以确定SOD在HCV介导的肝癌发生中的作用，并确定通过比较原蛋白分析的慢性HCV感染和SOD缺乏。将使用已建立的人肝细胞系，原代人肝细胞，HCV转基因小鼠和Cuznsod缺乏小鼠进行体外和体内研究，以确定HCV蛋白对ROS产生，钙稳态以及氧化还原敏感信号分子的活化的影响。一种遗传方法将用于降低HCV转基因小鼠中的SOD水平，以调节HCC发育的过程。此外，将实施不同的蛋白质组学工具和程序，以识别容易受到HCV转基因和Cuznsod缺乏小鼠氧化修饰的分子。