Role of microRNAs in the SV40 infectious cycle

描述(由申请人提供)：疱疹和多瘤病毒家族中的许多成员(如果不是所有成员)编码microRNAs(MiRNAs)。MiRNAs通过与特定的病毒或细胞靶向的mRNAs结合并抑制其表达而发挥作用。MiRNA介导的基因调控参与了重要的细胞过程，如肿瘤的发生。我们实验室最近的工作表明，由猿猴病毒40(SVmiRNA)编码的miRNAs能够为经历干扰素应答的感染细胞提供生长优势。此外，编码SVmiRNAs的基因的表达阻止了干扰素介导的细胞凋亡，这意味着在逃避宿主抗病毒防御方面发挥了重要作用。我们还发现了几个致癌的细胞miRNAs，它们是在感染SV40时诱导的。虽然这项工作指出了miRNAs在DNA肿瘤病毒生命周期中的重要作用，但SV40如何诱导病毒和细胞miRNAs表达以及如何防止细胞凋亡和促进转化的机制尚不清楚。这项建议的目的是确定miRNAs对多瘤病毒感染性和病毒诱导转化的贡献。为此，提出了三个具体目标。这些特定的目的提出了遗传和生化技术来：(1)确定干扰素途径中负责多瘤病毒诱导的细胞凋亡的成分。(2)确定多瘤病毒miRNA基因产物阻止干扰素诱导的细胞凋亡的机制。(3)确定病毒诱导的致癌细胞miRNAs在多瘤病毒复制和转化中的作用。公共卫生相关性：病毒介导的基因调控对致病性至关重要。本项目的目的是了解microRNA介导的基因调控在猿猴病毒40诱导的转化和感染循环中的作用。这项研究产生的知识可能适用于其他DNA肿瘤病毒及其相关的人类疾病。

DESCRIPTION (provided by applicant): Many, if not all members of the Herpes and Polyoma virus families encode microRNAs (miRNAs). miRNAs function by binding to specific viral or cellular target mRNAs and inhibiting their expression. miRNA- mediated gene regulation has been implicated in important cellular processes such as tumorigenesis. Recent work from our laboratory has demonstrated that the miRNAs encoded by Simian Virus 40 (SVmiRNA) function to provide a growth advantage to infected cells undergoing an interferon response. Furthermore, expression of the gene encoding the SVmiRNAs prevents interferon-mediated apoptosis, implying an important role in evading a host antiviral defense. We have also uncovered several oncogenic cellular miRNAs that are induced upon infection with SV40. Although this work points to an important role for miRNAs in DNA tumor viral lifecycles, the mechanism of how SV40 induces expression of viral and cellular miRNAs and how this prevents apoptosis and contributes to transformation is not understood. The goal of this proposal is to determine the contribution of miRNAs to Polyomaviral infectivity and viral-induced transformation. To this end, three specific aims are proposed. These specific aims propose genetic and biochemical techniques to: (1) Identify the components of the interferon pathway that are responsible for Polyomaviral-induced apoptosis. (2) Determine the mechanism by which the Polyomaviral miRNA gene products prevent interferon-induced apoptosis. (3) Determine the role of virally-induced oncogenic cellular miRNAs in Polyomavirus replication and transformation. PUBLIC HEALTH RELEVANCE: Viral-mediated gene regulation is critical for pathogenicity. The goal of this project is to understand the role of microRNA-mediated gene regulation in the Simian Virus 40-induced transformation and the infectious cycle. Knowledge generated from this research may be applicable to other DNA tumor viruses and their associated human diseases.