Pathogenesis of ovine betaretroviruses

致癌逆转录病毒的研究对我们理解癌症的遗传和分子基础做出了重大贡献，这一领域的研究继续揭示出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贝塔病毒的细胞进入和致癌作用，揭示逆转录病毒发病机制中的新概念和潜在的变革性概念。绵羊Jaagsiekte逆转录病毒(JSRV)和流行性鼻肿瘤病毒(ENTV)分别是绵羊肺腺癌(OPA)和流行性鼻腺癌(ENA)的病原体，在致癌逆转录病毒中是独一无二的。它们是已知的唯一感染呼吸道的逆转录病毒，与大多数可复制的致癌逆转录病毒不同，大多数致癌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而致癌，JSRV和ENTV的包膜(Env)糖蛋白作为有效的癌基因发挥作用，代表了一种全新的病毒转化机制。Env介导的转化涉及多种信号转导途径，其中细胞质尾部(CT)和该区域内的Yxx基序对转化起关键作用。然而，目前还不清楚哪些细胞蛋白与JSRV和ENTV Env蛋白相互作用，在体外诱导细胞转化或在动物体内形成肿瘤，也不知道JSRV和ENTV Env CT中的Yxx基序如何促进转化。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入病毒，但它们具有不同的肿瘤诱导能力，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诱导肺癌和鼻癌的分子机制，特别是关注Env在细胞转化和组织趋向性中的作用。我的短期目标是回答以下问题：1)Yxx基序在Jenv和Eenv介导的转化中扮演什么角色？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的不同组织趋向性？4)ENTV是否利用共同受体来介导病毒的附着和进入？这项研究计划将专业知识与安大略省兽医学院独有的大型动物模型与分子病毒学方法相结合，以了解病毒在不同上皮细胞群中转化的机制。这项研究准备揭示贝塔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.