Molecular Basis of Cytokine-induced Clearance of HBV RNA

细胞因子诱导 HBV RNA 清除的分子基础

• 批准号: 6339873
• 负责人: Susan L. Uprichard
• 金额: $ 4.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6339873
• 关键词: Adenoviridae; cytokine; cytotoxic T lymphocyte; genetic mapping; genetically modified animals; hepatitis B virus group; host organism interaction; laboratory mouse; liver cells; microorganism immunology; molecular cloning; protein sequence; recombinant virus; transfection /expression vector; virus RNA

DESCRIPTION:(Adapted from the Investigator's abstract):Induction of cytokines in the mouse liver can cause the disappearance of HBV RNA by a post-transcriptional mechanism. This suggest that cytokines produced in the liver of infected patients can suppress viral gene expression. Most likely this involves inducing the hepatocytes to become participants in the antiviral process through activation of genes and/or gene products that consequently "cure" the cell. Identification of the intracellular mechanisms responsible for this antiviral effect is the long term goal of which the proposed work is a part. The following studies focus on defining viral RNA target elements and intracellular proteins that mediate this cytokine regulation. Previously the ceJiular La protein was observed to be cleaved coincident with the inhibition of HBV RNA. We propose to do a more functional-based analysis to test the hypothesis that HBV gene expression is in fact regulated by La. In addition, by using a general mutagenesis approach we will test the hypothesis that a cytokine-responsive target element(s) may exist within the HBV transcripts which renders these RNAs susceptible to down-regulation. Importantly, we are proposing to do these molecular analyses in vivo using the HBV transgenic mouse model as the in vivo nature of this system suggests that the results might closely reflect what occurs during a natural infection. If we can learn how the immune system is able in some cases to successfully combat the virus, we may be able to mimic that strategy or trigger that antiviral pathway in all infected patients. Ultimately, such knowledge could also prove to be relevant to the treatment of other persistent hepatic viral infections, particularly HCV.

描述：(根据研究人员摘要改编)：在小鼠肝脏中诱导细胞因子可以通过转录后机制导致HBVRNA的消失。这表明，感染患者肝脏中产生的细胞因子可以抑制病毒基因的表达。这很可能包括通过激活基因和/或基因产物来诱导肝细胞成为抗病毒过程的参与者，从而“治愈”细胞。确定这种抗病毒作用的细胞内机制是长期目标，拟议的工作是其中的一部分。下面的研究集中在确定病毒RNA靶分子和介导这种细胞因子调节的细胞内蛋白。以前，观察到cejiular La蛋白被切割，这与对HBVRNA的抑制一致。我们建议做一个更基于功能的分析，以检验乙肝病毒基因表达实际上受La调控的假设。此外，通过使用一般的突变方法，我们将检验这一假设，即在乙肝病毒转录本中可能存在一个细胞因子反应的靶元件(S)，使这些RNA容易受到下调。重要的是，我们建议使用乙肝转基因小鼠模型在体内进行这些分子分析，因为这个系统的在体性质表明，结果可能密切反映了自然感染期间发生的事情。如果我们能够了解免疫系统如何在某些情况下成功地对抗病毒，我们可能能够在所有感染的患者中模仿这一策略或触发抗病毒途径。最终，这些知识也可能被证明与其他持续性肝病毒感染的治疗有关，特别是丙型肝炎病毒。