Pathogenesis of ovine betaretroviruses

致癌逆转录病毒的研究为我们理解癌症的遗传和分子基础做出了重大贡献，该领域的研究继续揭示对基本细胞过程的新见解。我的研究项目旨在通过研究绵羊β逆转录病毒的细胞进入和肿瘤发生来揭示逆转录病毒发病机制中的新的和潜在的变革性概念。绵羊肺腺瘤病毒（Jaagsiekte sheep retrovirusJSRV）和地方性鼻肿瘤病毒（ENTV）分别是引起绵羊肺腺癌（ovine pulmonary adenocarcinoma OPA）和地方性鼻腺癌（ENA）的两种独特的致瘤逆转录病毒。它们是已知感染呼吸道的唯一逆转录病毒，并且不像大多数具有复制能力的致癌逆转录病毒，其通过插入激活细胞原癌基因或通过获得细胞原癌基因而引起癌症，JSRV和ENTV的包膜（Env）糖蛋白作为代表病毒转化的全新机制的强效癌基因起作用。Env介导的转化中涉及几种信号转导途径，并且已知该区域内的胞质尾（CT）和特别是Yxx基序对于转化是关键的。然而，尚不清楚什么细胞蛋白与JSRV和ENTV Env蛋白相互作用以诱导体外细胞转化或动物中的肿瘤形成，也不知道JSRV和ENTV Env CT中的Yxx基序如何促成转化。此外，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。因此，我的研究计划的长期目标是更清楚地了解JSRV和ENTV诱导肺癌和鼻腔癌的分子机制，特别关注Env在细胞转化和组织向性中的作用。我的短期目标是回答以下问题：1）Yxx基序在Jenv和Eenv介导的转化中起什么作用？2)与Jenv和Eenv相互作用的蛋白质如何发挥作用以促进细胞转化？3)病毒基因组的哪个区域负责JSRV和ENTV不同的组织嗜性？4)ENTV是否利用辅助受体介导病毒附着和进入？ 该研究计划结合了安大略兽医学院独特的大型动物模型的专业知识和分子病毒学方法，以了解不同上皮细胞群体中病毒转化的机制。这项研究有望揭示β逆转录病毒嗜性和进入的新机制，并可能揭示动物和人类呼吸道上皮癌治疗干预的潜在靶点。

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 Yxx 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 Yxx 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 Yxx 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.