Pathogenesis of ovine betaretroviruses

绵羊β逆转录病毒的发病机制

• 批准号: RGPIN-2018-04737
• 负责人: Wootton, Sarah
• 金额: $ 3.64万
• 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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=668901
• 关键词: Pathogenesis; ovine; betaretroviruses

The study of oncogenic retroviruses has contributed significantly to our understanding of the genetic and molecular basis of cancer and research in this area continues to reveal new insights into fundamental cellular processes. My research program aims to uncover novel and potentially transformative concepts in retroviral pathogenesis by studying cell entry and oncogenesis of ovine betaretroviruses. Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), the etiologic agents of ovine pulmonary adenocarcinoma (OPA) and enzootic nasal adenocarcinoma (ENA), respectively, are unique among oncogenic retroviruses. They are the only retroviruses known to infect the respiratory tract and unlike most replication-competent oncogenic retroviruses, which cause cancer by insertional activation of cellular proto-oncogenes or through acquisition of cellular proto-oncogenes, the envelope (Env) glycoproteins of JSRV and ENTV function as potent oncogenes representing an entirely novel mechanism of viral transformation. Several signal transduction pathways have been implicated in Env-mediated transformation and it is known that the cytoplasmic tail (CT) and specifically YxxØ motifs within this region are critical for transformation. However, it is still not clear what cellular proteins interact with the JSRV and ENTV Env proteins to induce cellular transformation in vitro or tumor formation in animals nor is it known how YxxØ motifs in the JSRV and ENTV Env CT contribute to transformation. Moreover, 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. The long-term objective of my research program, therefore, is a clearer understanding of the molecular mechanisms involved in the induction of lung and nasal cancer by JSRV and ENTV, with particular attention to the role of Env in cellular transformation and tissue tropism. My short-term objectives are to answer the following questions: 1) What role do YxxØ motifs play in Jenv- and Eenv-mediated transformation? 2) How do proteins that interact with Jenv and Eenv function to promote cellular transformation? 3) What region of the viral genome is responsible for the distinct tissue tropism of JSRV and ENTV? 4) Does ENTV utilize a co-receptor to mediate virus attachment and entry? ******This research program combines expertise with large animal models uniquely available at the Ontario Veterinary College with molecular virology approaches to yield an understanding of the mechanisms of viral transformation in distinct epithelial cell populations. This research is poised to uncover novel mechanisms for betaretrovirus tropism and entry and may reveal potential targets for therapeutic intervention in the treatment of respiratory epithelial cancers of animals and humans.

致癌逆转录病毒的研究为我们对癌症的遗传和分子基础的理解做出了重大贡献，该领域的研究不断揭示对基本细胞过程的新见解。绵羊β逆转录病毒（JSRV）和地方性鼻肿瘤病毒（ENTV）的细胞进入和肿瘤发生，绵羊肺腺癌（OPA）和地方性鼻腺癌（ENA）在致癌逆转录病毒中是独特的，它们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致癌逆转录病毒不同，后者通过插入激活细胞原癌基因或通过获得原癌基因而引起癌症。细胞原癌基因、JSRV 和 ENTV 的包膜 (Env) 糖蛋白作为强效癌基因发挥作用，代表了一种全新的病毒机制Env 介导的转化涉及多种信号转导途径，并且已知该区域内的细胞质尾 (CT) 和特别是 YxxØ 基序对于转化至关重要。 JSRV 和 ENTV Env 蛋白在体外诱导细胞转化或在动物中诱导肿瘤形成，也不知道 JSRV 和 ENTV Env CT 中的 YxxØ 基序如何促进转化。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，它们具有独特的肿瘤诱导能力，其原因尚不清楚，因此，我的研究计划的长期目标是更清楚地了解分子。我的短期目标是回答以下问题：1）YxxØ 基序发挥什么作用。在Jenv 和 Eenv 介导的转化？ 2) 与 Jenv 和 Eenv 相互作用的蛋白质如何促进细胞转化？ 3) 病毒基因组的哪个区域负责 JSRV 和 ENTV 的不同组织向性？ ******该研究项目将安大略兽医学院独有的大型动物模型的专业知识与分子病毒学方法相结合，以了解病毒的机制这项研究有望揭示β逆转录病毒趋向性和进入的新机制，并可能揭示动物和人类呼吸道上皮癌治疗干预的潜在靶标。