Dissecting the molecular pathways of MDV oncoprotein Meq for understanding pathogenesis and aid vaccine development

传染病在家禽养殖的各个环节造成直接和间接损失，其中由病毒引起的肿瘤性疾病是全球家禽业面临的主要经济问题。在鸡中引起肿瘤感染的致癌病毒是包括马立克氏病病毒（MDV）的疱疹病毒和包括网状内皮组织增生病病毒（REV）和禽白血病病毒（ALV）的逆转录病毒。马立克氏病（MD）是鸡的一种常见疾病，涉及瘫痪，并且通常由于高度恶性T淋巴瘤（白色血细胞的癌症）的生长而死亡。MD是由一种可传播的媒介MDV引起的。MDV具有很强的传染性，是全球家禽业的主要威胁。据估计，全世界因这一疾病造成的总损失高达20亿美元。目前，它是通过接种疫苗来控制的，每年有近220亿剂疫苗用于控制这种疾病。尽管广泛接种疫苗，但由于MDV的毒力不断增强，因此这种疾病的威胁正在增加，需要进行更多的基础研究来了解这种病毒导致癌症的机制，以制定更有效的控制方案。Meq是MDV致瘤的主要癌蛋白。之前，我们已经在癌细胞中鉴定了Meq targetome。在这项新的赠款提案中，将由Pirbright研究所和Roslin研究所联合进行，我们希望扩展这些研究，使用许多先进的方法，包括我们最近在实验室建立的CRISPR/Cas9基因组编辑和内源性蛋白的快速免疫沉淀质谱（RIME），获得Meq及其靶点在MDV诱导的肿瘤发生中的作用的详细信息。用于Meq相互作用组鉴定。这项研究对于了解这种病毒诱发癌症的机制非常重要，其中一些机制对于了解包括人类在内的其他物种的癌症非常有价值。最后，该项目的发现将对开发控制致癌病毒引起的癌症的新方法非常有价值。

Infectious diseases result in direct and indirect losses at various steps of poultry farming and amongst them neoplastic disease caused by viruses is a major economic problem faced by the poultry industry worldwide. The oncogenic viruses causing neoplastic infection in chickens are herpesviruses comprising of Marek's disease virus (MDV) and retroviruses comprising of reticuloendotheliosis virus (REV) and avian leucosis virus (ALV). Marek's disease (MD) is a common disease of chickens involving paralysis and commonly death from the growth of highly malignant T lymphomas (cancers of white blood cells). MD is caused by a transmissible agent MDV. MDV is very contagious and is a major threat to the poultry industry worldwide. The estimated total loss from this disease worldwide is up to $2 billion. Presently, it is controlled by vaccination, and nearly 22 billion vaccine doses a year are used in an attempt to control the disease. Despite widespread vaccination, the threat from this disease is on increase due to continued evolution of MDV towards greater virulence, and more fundamental studies to understand the mechanisms by which this virus causes cancer is needed to develop more effective control programmes. Meq is the major oncoprotein in MDV induced tumorigenesis. Previously, we have identified Meq targetome in cancer cells. In this new grant proposal, to be carried out jointly between the Pirbright Institute and Roslin Institute, we want to extend these studies to obtain detailed information on the role of Meq and its targets in MDV induced oncogenesis using a number of advanced approaches including CRISPR/Cas9 genome editing we have recently established in the lab and rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) for Meq interactome identification. The study is very important to understand the mechanisms by which this virus induces cancer, some of which are valuable in understanding cancer in other species including humans. Finally, the findings from the project will be very valuable in developing new approaches for the control of cancers caused by oncogenic viruses.