Role of SOCS3 in HCV Interferon Resistance

SOCS3 在 HCV 干扰素抵抗中的作用

• 批准号: 6953989
• 负责人: Chen Liu
• 金额: $ 7.28万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953989
• 关键词: JAK kinase; biological signal transduction; cell line; cytokine; drug resistance; gene expression; genetic promoter element; hepatitis C; hepatitis C virus; interferons; liver cells; transcription factor; virus protein

DESCRIPTION (provided by applicant): This proposal is a branch out pilot study that is closely related to the K08 project. The primary goal of the K08 project is to study the mechanisms of antiviral cytokines. During this study, we have gained significant insights into the interferon signaling mechanisms in liver cells, which prompts us to propose this pilot project to study the interactions of the Hepatitis C viral (HCV) proteins and interferon signaling molecules, and their role in interferon resistance. The current proposal will significantly contribute to the overall goal of the K08. The R03 support will allow me to gain additional resources to successfully achieve the career development goal: being a fully independent investigator. HCV infection is a major chronic liver disease that is a rapidly increasing public health problem. Without an effective vaccine being available, the current treatment is combination therapy with interferon (IFN) and Ribavirin, which is only partially effective. Despite substantial research, the underlying molecular mechanisms for interferon resistance are not fully understood. The outcome of IFN-based treatment is undoubtedly related to the interaction of the virus and the host. Several studies have demonstrated that viral proteins can modulate cellular response to IFN, which may be a potential mechanism of IFN resistance. However, little is known about the mechanisms of such interactions. This proposal will focus on the mechanisms of host cellular factor-viral protein interactions in HCV interferon resistance. Our hypothesis is that the negative regulators of the JAK-STAT pathway may play a critical role in HCV interferon resistance, and the HCV core protein may have an impact on the expression of these regulators. This hypothesis will be tested by two specific aims: 1. To determine the role of SOCS3 in IFN resistance and to define the mechanisms by which SOCS3 regulates STAT activation; 2. To determine the mechanisms by which HCV core protein regulates SOCS3 expression. These two specific aims will allow us to gain insights into the interactions between the cell signaling molecules and viral proteins and their role in IFN response in liver cells. The conclusions of our proposed study will permit us to launch further experimentation aimed at improving IFN treatment efficacy and circumventing IFN resistance.

描述（由申请人提供）： 该提案是一项与K08项目密切相关的分支机构试点研究。 K08项目的主要目标是研究抗病毒细胞因子的机制。在这项研究中，我们对肝细胞中的干扰素信号传导机制有了重大的见解，这促使我们提出了该试验项目，以研究丙型肝炎病毒（HCV）蛋白（HCV）蛋白和干扰素信号分子的相互作用，以及它们在干扰素耐药性中的作用。当前的提案将大大促进K08的整体目标。 R03的支持将使我能够获得更多的资源，以成功实现职业发展目标：成为完全独立的研究者。 HCV感染是一种主要的慢性肝病，是公共卫生问题迅速增加。如果没有有效的疫苗，目前的治疗方法是与干扰素（IFN）和利巴韦林的联合治疗，这仅是部分有效的。尽管进行了大量研究，但尚未完全了解干扰素耐药性的基本分子机制。基于IFN的治疗的结果无疑与病毒和宿主的相互作用有关。几项研究表明，病毒蛋白可以调节对IFN的细胞反应，这可能是IFN抗性的潜在机制。但是，对这种相互作用的机制知之甚少。该建议将重点关注HCV干扰素耐药性中宿主细胞因子 - 病毒蛋白相互作用的机制。我们的假设是，JAK-STAT途径的负调节剂可能在HCV干扰素耐药性中起关键作用，并且HCV核心蛋白可能会影响这些调节剂的表达。该假设将通过两个具体目的来检验：1。确定SOCS3在IFN抗性中的作用并定义SOCS3调节统计激活的机制； 2。确定HCV核蛋白调节SOCS3表达的机制。这两个特定的目标将使我们能够深入了解细胞信号分子与病毒蛋白之间的相互作用及其在肝细胞中IFN反应中的作用。我们提出的研究的结论将使我们能够进行进一步的实验，以提高IFN治疗功效并规避IFN抗性。