Pathogenesis of enzootic nasal tumor virus (ENTV)

地方性鼻肿瘤病毒（ENTV）的发病机制

• 批准号: 355661-2008
• 负责人: Wootton, Sarah
• 金额: $ 2.91万
• 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: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=515189
• 关键词: Pathogenesis; enzootic; nasal; tumor; virus

Animal models of retrovirus-induced tumors have provided us with much of the foundation for our current understanding of the oncogenic process. Two economically important retroviruses associated with tumors of secretory respiratory epithelial cells are the Jaagsiekte sheep retrovirus (JSRV) and Enzootic nasal tumor virus (ENTV) of sheep and goats. While JSRV and ENTV are highly related betaretroviruses that utilize the same cell surface receptor for virus entry, they have distinct tumor-inducing capabilities. JSRV transforms alveolar type II pneumocytes, while ENTV transforms nasal epithelial cells. The reason for this is not known. This proposal addresses the hypothesis that induction of tissue-specific tumor formation in the ovine host is either a function of cell-restricted activity of the long terminal repeat (LTR) or due to the fact that ENTV and JSRV require a coreceptor for virus entry and differences in affinity or coreceptor usage determines cellular tropism. To address these hypotheses, a molecular clone of ENTV will be constructed and used to generate infectious virus for in vivo studies. Upon demonstration that ENTV is the etiologic agent of enzootic nasal adenocarcinoma, a series of chimeric viruses generated via the exchange of genetic material between JSRV and ENTV will be constructed and used to map genetic elements responsible for tissue-specific tumor formation. Specifically, the potential for coreceptor usage and restricted LTR activity will be addressed in these experiments. It is anticipated that this research program will contribute to our understanding of virally-induced cancers, uncover a potentially novel mechanism for retrovirus entry, and shed light on the mechanisms governing neoplastic transformation of secretory respiratory epithelial cells. Currently, no antemortem diagnostic tools are available for ENTV. Therefore, creating an animal model for ENTV infection allows for analysis of the cellular and tissue distribution of ENTV and subsequent identification of sensitive template sources for ENTV nucleic acid amplification. PCR-based diagnostic assays could then be developed and implemented in test and removal programs aimed at eradicating ENTV from Canadian sheep and goat flocks.

逆转录病毒诱导肿瘤的动物模型为我们目前理解致癌过程提供了许多基础。与分泌性呼吸道上皮细胞肿瘤相关的两种经济上重要的逆转录病毒是绵羊Jaagsiekte逆转录病毒（JSRV）和绵羊和山羊的地方性鼻肿瘤病毒（ENTV）。虽然JSRV和ENTV是高度相关的β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。JSRV转化肺泡II型肺细胞，而ENTV转化鼻上皮细胞。原因尚不清楚。这一提议解决了这样的假设，即在绵羊宿主中诱导组织特异性肿瘤形成是长末端重复序列（LTR）的细胞限制性活性的函数，或者是由于ENTV和JSRV需要辅助受体才能进入病毒，亲和力或辅助受体使用的差异决定了细胞嗜性。为了解决这些假设，将构建ENTV的分子克隆并用于产生用于体内研究的感染性病毒。在证明ENTV是地方性鼻腺癌的病原体后，将构建通过JSRV和ENTV之间的遗传物质交换产生的一系列嵌合病毒，并用于绘制负责组织特异性肿瘤形成的遗传元件。 具体而言，将在这些实验中解决辅助受体使用和限制LTR活性的可能性。预计这项研究计划将有助于我们了解病毒诱导的癌症，揭示一种潜在的新机制逆转录病毒进入，并阐明分泌性呼吸道上皮细胞的肿瘤转化机制。目前，没有死前诊断工具可用于ENTV。因此，创建ENTV感染的动物模型允许分析ENTV的细胞和组织分布，并随后鉴定用于ENTV核酸扩增的敏感模板来源。然后，可以开发基于PCR的诊断检测方法，并在旨在从加拿大绵羊和山羊群中根除ENTV的测试和清除计划中实施。