Role of viral microRNAs in Kaposi´s Sarcoma-associated Herpesvirus (KSHV) infection and KSHV-associated Disease

卡波西肉瘤相关疱疹病毒（KSHV）是内皮细胞和B细胞来源的几种肿瘤的病原体。这些恶性肿瘤中的大多数肿瘤细胞处于潜伏感染状态，这是病毒生命周期的一个阶段，在此期间只有少数病毒基因表达。因此，认为潜伏基因在肿瘤发生的发生和/或进展中起主要作用。最近，我们和其他人发现了几种潜在表达的KSHV-microRNA。MicroRNA是一类能够下调mRNA表达的新型小分子RNA，已成为许多细胞过程如分化、增殖和凋亡的重要调节因子。此外，microRNA在人类癌症中经常失调，最近的证据表明它们可以作为肿瘤抑制因子以及原癌基因。我们推测KSHV编码的microRNA在病毒的生命周期中起着至关重要的作用，并且可能有助于KSHV相关疾病的发病机制。拟议的项目旨在阐明KSHV-microRNA的功能，通过i）识别细胞mRNA靶点，ii）研究microRNA表达的表型后果，iii）定义KSHV microRNA在从头感染，潜伏期建立和裂解复制过程中的重要性。

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of several tumors of endothelial and B cell origin. The majority of tumor cells in these malignancies are in a latent state of infection, a stage of the viral lifecycle during which only a few viral genes are expressed. Consequently, it is thought that latency genes play a major role in the onset and/or progression of tumorigenesis. Recently, we and others have discovered several latently expressed KSHV-microRNAs. MicroRNAs, a novel class of small RNAs able to downregulate mRNA expression, have emerged as important regulators of many cellular processes such as differentiation, proliferation and apoptosis. Furthermore, microRNAs are frequently deregulated in human cancers, and recent evidence suggest they can act as tumor suppressors as well as proto-oncogenes. We hypothesize that KSHV-encoded microRNAs play a crucial role in the viral lifecycle and furthermore might contribute to the pathogenesis of KSHV-associated disease. The proposed project aims at elucidating the functions of KSHV-microRNAs by i) identifying cellular mRNA targets, ii) investigating phenotypic consequences of microRNA expression and iii) defining the importance of KSHV microRNAs during de novo infection, latency establishment and lytic replication.