Pathogenesis of ovine betaretroviruses

逆转录病毒诱导的肿瘤动物模型为我们目前对肿瘤发生的理解提供了很大的基础。这项建议集中在两个经济上重要的致癌绵羊逆转录病毒，Jaagsiekte绵羊逆转录病毒(JSRV)，它是绵羊肺腺癌的病原体，以及地方性鼻瘤病毒(ENTV)，它与地方性鼻腺癌有关。JSRV和ENTV在致癌逆转录病毒中是独一无二的，因为它们是已知的唯一感染呼吸道的逆转录病毒，不同于大多数复制能力强的逆转录病毒，JSRV和ENTV通过插入激活细胞原癌基因或通过获取细胞原癌基因而致癌，JSRV和ENTV的包膜蛋白是致癌的，因此代表了一种独特的转化机制。有几条信号通路参与了Env介导的转化，细胞质尾部(CT)，特别是该区域的Yxx？基序是转化所必需的。大多数逆转录病毒Env蛋白在其CT中含有Yxx？基序，作为内吞作用、细胞内靶向或病毒粒子掺入信号。Yxx？基序如何对JSRV和ENTV Env的转化做出贡献尚不清楚。虽然JSRV和ENTV是高度相关的逆转录病毒，它们利用相同的细胞表面受体进入病毒，但它们具有不同的肿瘤诱导能力，其原因尚不清楚。鉴于这两种病毒之间的高核苷酸同源性，这为研究疾病趋向性的决定因素提供了一个独特的系统，特别是因为我们的研究表明，LTR和Env本身都不决定趋向性。出于这些原因，我们建议进行实验来研究疾病趋向性的决定因素，并确定在Env的CT中Env结合伙伴和基序在细胞转化、病毒进入和病毒组装中的作用。预计这项研究计划将有助于我们理解病毒诱导的癌症，揭示逆转录病毒组装的潜在新机制，并阐明控制呼吸道上皮肿瘤转化的机制。

Animal models of retrovirus-induced tumors have provided us with much of the foundation for our current understanding of oncogenesis. This proposal focuses on two economically important oncogenic ovine retroviruses, jaagsiekte sheep retrovirus (JSRV), which is the etiologic agents of ovine pulmonary adenocarcinoma, and enzootic nasal tumor virus (ENTV), which is associated with enzootic nasal adenocarcinoma. JSRV and ENTV are unique among oncogenic retroviruses as they are the only retroviruses known to infect the respiratory tract and, unlike most replication-competent retroviruses, which cause cancer by insertional activation of cellular proto-oncogenes or through acquisition of cellular proto-oncogenes, the envelope (Env) protein of JSRV and ENTV is oncogenic and thus represents a unique mechanism of transformation. Several signalling pathways have been implicated in Env-mediated transformation and the cytoplasmic tail (CT), in particular YxxØ motifs in this region, are essential for transformation. Most retroviral Env proteins harbor YxxØ motifs in their CT that act as endocytosis, intracellular targeting, or virion incorporation signals. How YxxØ motifs contribute to transformation by JSRV and ENTV Env is not known. While JSRV and ENTV are highly related retroviruses that utilize the same cell surface receptor for virus entry, they have distinct tumor-inducing capabilities and the reason for this is not known. Given the high nucleotide identity shared between these two viruses, this provides an unique system for studying determinants of disease tropism especially because our research efforts suggest that neither the LTR nor the Env alone dictate tropism. For these reasons we propose experiments to investigate the determinants of disease tropism, and to ascertain the role of Env binding partners and motifs within the CT of Env in cellular transformation, virus entry, and virus assembly. It is anticipated that this research program will contribute to our understanding of virally-induced cancers, uncover a potentially novel mechanism for retrovirus assembly, and shed light on mechanisms governing neoplastic transformation of respiratory epithelium.