Pathogenesis of ovine betaretroviruses

绵羊β逆转录病毒的发病机制

• 批准号: 355661-2013
• 负责人: Wootton, Sarah
• 金额: $ 2.62万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=549795
• 关键词: Pathogenesis; ovine; betaretroviruses

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.

逆转录病毒诱导肿瘤的动物模型为我们目前了解肿瘤发生提供了很多基础。该提案重点关注两种经济上重要的致癌绵羊逆转录病毒，即 jaagsiekte 绵羊逆转录病毒（JSRV），它是绵羊肺腺癌的病原体。与地方性鼻腺癌相关的地方性鼻肿瘤病毒 (ENTV) JSRV 和 ENTV 在致癌逆转录病毒中是独一无二的。 JSRV 和 ENTV 是唯一已知感染呼吸道的逆转录病毒，与大多数具有复制能力的逆转录病毒（通过插入激活细胞原癌基因或通过获取细胞原癌基因引起癌症）不同，JSRV 和 ENTV 的包膜 (Env) 蛋白是致癌性，因此代表了一种独特的转化机制，一些信号通路涉及 Env 介导的转化和细胞质尾 (CT)，特别是 YxxØ 基序。大多数逆转录病毒 Env 蛋白在其 CT 中含有 YxxØ 基序，可充当胞吞作用、细胞内靶向或病毒粒子掺入信号。 YxxØ 基序如何促进 JSRV 和 ENTV Env 的转化尚不清楚。是高度相关的逆转录病毒，利用相同的细胞表面受体进行病毒进入，它们具有不同的肿瘤诱导能力，但鉴于它们之间共享的高核苷酸同一性，其原因尚不清楚。这两种病毒，这为研究疾病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工作表明，LTR 和 Env 都不能单独决定向性。出于这些原因，我们建议进行实验来研究疾病向性的决定因素，并确定疾病向性的决定因素。 Env 结合伴侣和 Env CT 中的基序在细胞转化、病毒进入和病毒组装中的作用预计该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，并揭示了控制呼吸道上皮肿瘤转化的机制。