KSHV编码的vIRF1诱导内皮细胞迁移、侵袭与血管生成：miRNAs及其靶蛋白的作用与意义

卡波氏肉瘤（KS）是HIV感染者中最为常见的恶性肿瘤，AIDS-KS治疗困难，患者往往在两年内死亡。KS病理特征表现为内皮细胞增生与新生血管生成，其病原体是卡波氏肉瘤病毒（KSHV）。先前研究发现，KSHV编码的病毒干扰素调节因子1（vIRF1）能够诱导裸鼠体内肿瘤形成，然而机制并不清楚。我们近期的预试验也发现，vIRF1可以诱导内皮细胞迁移、侵袭与血管生成。因此我们提出科学假说：vIRF1通过调控宿主细胞的重要miRNAs分子及其靶向的关键蛋白来诱导内皮细胞迁移与血管生成，最终导致KS的发生。 .为了验证此假说，本项目拟通过体外细胞迁移及体内CAM和裸鼠PLUG试验等证实vIRF1能够诱导内皮细胞迁移、侵袭与血管生成；鉴定调控上述过程的关键蛋白及其下游信号通路；鉴定通过靶向关键蛋白介导上述过程的重要miRNAs分子。 .研究结果有助于阐明KS发病机理，为KS的治疗提供潜在的分子靶点。

Kaposi’s sarcoma (KS) is the most common malignant neoplasm associated with HIV/AIDS patients and AIDS-KS patients with treatment difficulties usually die in two years. KS starts as the proliferation of endothelial-type cells with the abnormal leaky blood vessel expansion. Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of KS. Previous studies demonstrated that KSHV encoded viral interferon regulatory factor 1 (vIRF1) could induce tumorigenesis in nude mice. However, the mechanisms of vIRF1-induced tumorigenesis remain unclear. Recently, the results of our preliminary tests have also shown that vIRF1 induced the migration, invasion and angiogenesis of endothelial cells. Therefore, the working hypothesis of this project is that vIRF1 can induce the migration and angiogenesis of endothelial cells through regulating important miRNAs of host cells and key proteins targeted by important miRNAs, which contributes to the occurrence of KS. .To test this hypothesis, we will perform the following specific aims: (1) To confirm that KSHV vIRF1 can induce the migration, invasion and angiogenesis of endothelial cells both in vitro and in vivo; (2) To identify the key proteins and downstream signal pathways participated in the process above mentioned; (3) To identify the critical miRNAs which target the key proteins involved in the process above mentioned..This study will contribute to clarify the pathogenic mechanisms of KS, which may provide the potential molecular targets for the treatment of KS.