Molecular Basis of Cytokine-induced Clearance of HBV RNA

描述：（改编自研究者的摘要）：小鼠肝脏中细胞因子的诱导可通过转录后机制导致HBV RNA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。最可能的是，通过激活基因和/或基因产物，诱导肝细胞参与抗病毒过程，从而“治愈”细胞。确定细胞内机制负责这种抗病毒作用是长期目标，其中提出的工作是一部分。接下来的研究重点是确定介导这种细胞因子调节的病毒RNA靶元件和细胞内蛋白。先前观察到ceJiular La蛋白在抑制HBV RNA的同时被切割。我们建议做一个更基于功能的分析来检验HBV基因表达实际上是由La调节的假设。此外，通过使用一般诱变方法，我们将测试假设，即在HBV转录本中可能存在细胞因子应答靶元件，使这些rna易于下调。重要的是，我们建议使用HBV转基因小鼠模型在体内进行这些分子分析，因为该系统的体内性质表明结果可能密切反映自然感染期间发生的情况。如果我们能够了解免疫系统在某些情况下是如何成功对抗病毒的，我们就可以模仿这种策略，或在所有感染患者中触发抗病毒途径。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。

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.