The contribution of Kaposi Sarcoma Herpesvirus K15 protein to virus-induced pathological angiogenesis

卡波西肉瘤疱疹病毒(KSHV)，又称人类疱疹病毒8型(HHV8)，是一种人类伽马疱疹病毒，可引起卡波西肉瘤(KS)、原发性渗出性淋巴瘤(PEL)和大多数多中心Castleman病(MCD)的浆细胞变异型。卡波西肉瘤是一种多/寡克隆性血管肿瘤，被认为起源于淋巴管内皮细胞。其组织学特征是潜伏感染KSHV的非典型内皮细胞，特别是典型的梭形细胞，以及血管渗漏的迹象，非典型内皮细胞显示内皮细胞-间充质转化(EndMT)迹象和明显的炎症反应。有几种病毒蛋白与这些不同的组织学异常有关。我们最近发现，KSHV K15蛋白可能在KSHV诱导的血管生成中发挥作用。K15蛋白是EB病毒(EBV)转化蛋白LMP1和LMP2A的远端功能和位置上的同源物。因此，本项目提案的目的是进一步阐明K15蛋白改变血管生成的分子机制，以便更好地了解其在KS发病中的作用。我们还想寻求初步结果，表明靶向K15诱导的信号级联以阻断其血管生成特性的可能性。

Kaposi Sarcoma Herpesvirus (KSHV), also known as Human Herpesvirus 8 (HHV8) is a human gammaherpesvirus and the cause of Kaposi Sarcoma (KS), primary effusion lymphoma (PEL) and most cases of the plasma cell variant of multicentric Castleman Disease (MCD). Kaposi Sarcoma is a poly-/oligoclonal vascular tumour and thought to be derived from lymphatic endothelial cells. Its histology is characterized by latently KSHV-infected atypical endothelial cells, in particular the characteristic spindle cells, as well as signs of a leaky vasculature, atypical endothelial cells exhibiting signs of endothelial-mesenchymal transition (EndMT) and pronounced inflammatory responses. Several viral proteins have been linked to these different histological abnormalities. We have recently shown that the KSHV K15 protein, a distant functional and positional homologue of the Epstein-Barr Virus (EBV) transforming proteins LMP1 and LMP2A, may play a role in KSHV-induced angiogenesis. The aim of this project proposal therefore is to further elucidate the molecular mechanisms by which the K15 protein may alter angiogenesis in order to better understand its contribution to KS pathogenesis. We also want to pursue preliminary results that indicate the possibility of targeting K15-induced signaling cascades in order to block its angiogenic properties.