Regulation of MicroRNA by Human Cytomegalovirus

描述：microRNAs(MiRNA)是最近发现的在细胞基因表达调控中具有重要作用的小分子(-21nT)RNA物种。这将有别于机制相关的细胞防御机制，后者通过非常相似的机制(小干扰RNA，或siRNA)介导，但针对外源mRNAs，如病毒表达的mRNAs。据预测，人类基因组将编码多达500到600个不同的miRNA基因。MiRNA调控的靶点包括参与发育阶段调控和细胞分化的基因。不同的细胞类型，例如神经细胞和干细胞，表达不同的miRNA群体，每个miRNA物种的表达和丰度不同。MiRNA活性明显表现为靶向mRNAs翻译减少。疱疹病毒是一种基因复杂的病毒，编码多达200个基因，其中只有大约40个参与复制和打包基因组以供传播的基本方面。其余的参与操纵细胞和组织环境，以确保短期复制成功和病毒在进化时间尺度上的生存。因此，这些基因产物在调节宿主细胞代谢和免疫反应方面发挥着广泛而深远的作用。人巨细胞病毒(HCMV)是一种重要的人类病原体，它具有遗传上最复杂的疱疹病毒基因组之一，以及相应的复杂生物学。这一应用旨在了解人巨细胞病毒感染与细胞miRNA基因表达和功能的关系。我们提出了两条研究路线：目的1：巨细胞病毒感染是否导致细胞miRNA物种表达的改变？目的2：病毒改变miRNA表达的生物学后果是什么？这里提出的工作的意义在于它开辟了一条与病毒使用和细胞过程操纵相关的研究新途径，该过程调节了一系列结果。这项工作的潜在长期结果包括改进的诊断方法和新的治疗策略。

DESCRIPTION: MicroRNAs (miRNA) are recently discovered small (-21 nt) RNA species that have important roles in regulation of cellular gene expression. This is to be distinguished from mechanistically related cellular defense mechanisms that are mediated via very similar mechanisms (small interfering RNA, or siRNA), but target exogenous mRNAs, such as those expressed by viruses. The human genome has been predicted to encode as many as 500 to 600 distinct miRNA genes. Targets of miRNA regulation include genes involved in regulation of developmental stages and in cellular differentiation. Different cell types, e.g., neuronal vs. stem cells, express miRNA populations that differ in representation and abundance of individual miRNA species. miRNA activity is manifest as reduced translation from the targeted mRNAs. Herpesviruses are genetically complex viruses that encode as many as 200 genes, of which only about 40 are involved in the fundamental aspects of replicating and packaging the genome for transmission. The remainder are involved in manipulating the cellular and organismal environment to ensure short-term replicative success and virus survival on an evolutionary time scale. Thus, these gene products exercise diverse and profound effects on regulation of host cell metabolism and immune responses. Human cytomegalovirus (HCMV) is an important human pathogen that has one of the genetically most complex herpesvirus genomes, and a correspondingly complex biology. This application is aimed at understanding the relationships between HCMV infection and the expression and function of cellular miRNA genes. We propose two lines of inquiry: Aim 1: Does HCMV infection result in altered expression of cellular miRNA species? Aim 2: What are the biological consequences of virally altered miRNA expression? The significance of the work proposed here rests on it opening a new avenue of research relating to viral use and manipulation of a cellular process that regulates a wide range of outcomes. Potential long-term outcomes of this work include improved diagnostic methods and novel therapeutic strategies.