Heme Oxygenase-1 and Hepatitis C
血红素加氧酶 1 和丙型肝炎
基本信息
- 批准号:7051949
- 负责人:
- 金额:$ 15.38万
- 依托单位:
- 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:2005-05-01 至 2008-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a global health problem, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma, superoxide and peroxide that arise during viral infection and damage hepatocytes and surrounding cells. Hepatocytes normally up-regulate oxidative defense enzymes to maintain redox balance and prevent injury. An important antioxidative enzyme is heme oxygenase-1 (HO-1) that is induced in response to oxidative stress in humans and animal models. Although the role of HO-1 in human liver disease has not been well-studied, available evidence suggests that the enzyme is usually up-regulated in response to injury. In contrast, recent data by our group have shown that HO-1 expression is down-regulated in HCV infected liver samples and that the HCV core protein transcriptionally down-regulates the enzyme in vitro. Collectively, these data suggest that suppression of HO-1 expression by HCV may contribute to hepatic injury. Our overall objective is to determine the role and importance of HO-1 in HCV liver disease and the pathologic consequences that result when the enzyme is down regulated by HCV. Our central hypothesis is that HO-1 is an important hepatocellular defense enzyme that overall prevents hepatocyte injury. Hepatitis C virus transcriptionally down regulates expression of HO-1 during chronic infection, which alters the susceptibility and response of the hepatocyte to injury. Using a large human liver sample bank for the in vivo studies and a variety of HCV protein and full length viral constructs in vitro, we will test the central hypothesis and accomplish the major objective by undertaking experiments of three specific aims: 1) We will test the hypothesis that down regulation of HO-1 in HCV liver disease is significantly related to, and important for hepatocyte injury in vivo. 2) We will test the hypothesis that HO-1 is transcriptionally down-regulated in contrast to HO-2 in Huh-7.5 hepatocytes expressing FL HCV replicons. 3) We will test the hypothesis that hepatocytes expressing FL HCV replicons are more sensitive to cellular injury and oxidative stress. We also hypothesize that over-expression of HO-1 will at least partially reverse the untoward effects of FL HCV replication and expression on cellular oxidative redox balance. These experiments will increase our understanding of the importance of HO-1 in HCV and other liver diseases and the putative injurious consequences that result when the enzyme is down-regulated. Further study of the regulation of HO-1 expression by HCV will lay the foundation for-improved therapeutic options1 for patients with chronic HCV disease such as targeted antioxidant gene therapy and selective antioxidants.
描述(由申请人提供):丙型肝炎病毒(HCV)是一种全球性健康问题,可引起慢性肝炎、肝硬化和肝细胞癌,在病毒感染期间产生超氧化物和过氧化物,并损害肝细胞和周围细胞。肝细胞通常上调氧化防御酶以维持氧化还原平衡并防止损伤。一种重要的抗氧化酶是血红素加氧酶-1(HO-1),其在人类和动物模型中响应于氧化应激而被诱导。虽然HO-1在人类肝脏疾病中的作用尚未得到充分研究,但现有证据表明,该酶通常在损伤时上调。相反,我们小组最近的数据表明,HO-1的表达在HCV感染的肝脏样品中下调,并且HCV核心蛋白在体外转录下调该酶。总的来说,这些数据表明,HO-1表达的抑制HCV可能有助于肝损伤。我们的总体目标是确定HO-1在HCV肝病中的作用和重要性,以及当酶被HCV下调时所导致的病理后果。我们的中心假设是HO-1是一种重要的肝细胞防御酶,可全面预防肝细胞损伤。丙型肝炎病毒在慢性感染期间转录下调HO-1的表达,这改变了肝细胞对损伤的易感性和反应。使用用于体内研究的大型人肝样品库和多种HCV蛋白和全长病毒构建体,我们将通过进行三个特定目的的实验来测试中心假设并实现主要目标:1)我们将测试HCV肝病中HO-1的下调与体内肝细胞损伤显著相关并且对肝细胞损伤重要的假设。2)我们将检验HO-1在表达FL HCV复制子的Huh-7.5肝细胞中与HO-2相比转录下调的假设。3)我们将检验表达FL HCV复制子的肝细胞对细胞损伤和氧化应激更敏感的假设。我们还假设HO-1的过表达将至少部分逆转FL HCV复制和表达对细胞氧化还原平衡的不利影响。这些实验将增加我们对HO-1在HCV和其他肝脏疾病中的重要性的理解,以及当酶被下调时可能导致的有害后果。进一步研究HCV对HO-1表达的调控将为改善慢性HCV疾病患者的治疗选择1奠定基础,如靶向抗氧化基因治疗和选择性抗氧化剂。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Restoration of type I interferon expression by heme and related tetrapyrroles through inhibition of NS3/4A protease.
- DOI:10.1093/infdis/jit338
- 发表时间:2013-11
- 期刊:
- 影响因子:0
- 作者:Zhao-feng Zhu;M. Mathahs;W. Schmidt
- 通讯作者:Zhao-feng Zhu;M. Mathahs;W. Schmidt
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WARREN N SCHMIDT其他文献
WARREN N SCHMIDT的其他文献
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{{ truncateString('WARREN N SCHMIDT', 18)}}的其他基金
Neoplastic interactions of hepatitis C virus with telomerase.
丙型肝炎病毒与端粒酶的肿瘤相互作用。
- 批准号:
10047694 - 财政年份:2009
- 资助金额:
$ 15.38万 - 项目类别:
Anti HCV Protease Activities of Metalloporphyrins
金属卟啉的抗HCV蛋白酶活性
- 批准号:
8803233 - 财政年份:2009
- 资助金额:
$ 15.38万 - 项目类别:
Anti HCV Protease Activities of Metalloporphyrins
金属卟啉的抗HCV蛋白酶活性
- 批准号:
8666517 - 财政年份:2009
- 资助金额:
$ 15.38万 - 项目类别:
Heme Oxygenase-1 Inhibition of Hepatitis C Replication
血红素加氧酶 1 抑制丙型肝炎复制
- 批准号:
8262609 - 财政年份:2009
- 资助金额:
$ 15.38万 - 项目类别:
Heme Oxygenase-1 Inhibition of Hepatitis C Replication
血红素加氧酶 1 抑制丙型肝炎复制
- 批准号:
8195610 - 财政年份:2009
- 资助金额:
$ 15.38万 - 项目类别:
Anti HCV Protease Activities of Metalloporphyrins
金属卟啉的抗HCV蛋白酶活性
- 批准号:
8441039 - 财政年份:2009
- 资助金额:
$ 15.38万 - 项目类别:
Heme Oxygenase-1 Inhibition of Hepatitis C Replication
血红素加氧酶 1 抑制丙型肝炎复制
- 批准号:
7686494 - 财政年份:2009
- 资助金额:
$ 15.38万 - 项目类别:
Heme Oxygenase-1 Inhibition of Hepatitis C Replication
血红素加氧酶 1 抑制丙型肝炎复制
- 批准号:
7787492 - 财政年份:2009
- 资助金额:
$ 15.38万 - 项目类别:
THALIDOMIDE IN PATIENTS WITH ACUTE ALCOHOLIC HEPATITIS
沙利度胺用于急性酒精性肝炎患者
- 批准号:
7201331 - 财政年份:2005
- 资助金额:
$ 15.38万 - 项目类别:
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