Pathogenesis of ovine betaretroviruses

逆转录病毒诱导肿瘤的动物模型为我们目前对肿瘤发生的理解提供了许多基础。该建议的重点是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），这是绵羊肺腺癌的病原体，和地方性鼻肿瘤病毒（ENTV），这是与地方性鼻腺癌。JSRV和ENTV在致癌逆转录病毒中是独特的，因为它们是已知感染呼吸道的唯一逆转录病毒，并且与通过细胞原癌基因的插入激活或通过获得细胞原癌基因引起癌症的大多数具有复制能力的逆转录病毒不同，JSRV和ENTV的包膜（Env）蛋白是致癌的，因此代表了独特的转化机制。Env介导的转化中涉及几种信号传导途径，并且细胞质尾（CT），特别是该区域中的Yxxx基序，对于转化是必需的。大多数逆转录病毒Env蛋白在它们的CT中具有Yxxx3基序，其充当内吞作用、细胞内靶向或病毒体掺入信号。目前尚不清楚YxxxB1基序如何促进JSRV和ENTV Env的转化。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行病毒进入，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共享的高核苷酸同一性，这为研究疾病嗜性的决定因素提供了独特的系统，特别是因为我们的研究工作表明，LTR和Env都不能单独决定嗜性。出于这些原因，我们提出的实验，以调查疾病嗜性的决定因素，并确定的作用Env的CT内的Env的结合伙伴和基序在细胞转化，病毒进入，和病毒组装。预计这项研究计划将有助于我们了解病毒诱导的癌症，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.