Dissecting the pathogenesis of ovine pulmonary adenocarcinoma with RNA-Seq

这项提案涉及绵羊的一种名为绵羊肺腺癌(OPA)的疾病，这种疾病是由一种名为JSRV的病毒引起的。JSRV类似于许多其他病毒(如流感)通过空气传播，并感染肺部细胞，在那里它触发癌症的生长。OPA是一种影响英国和其他许多国家羊群的重要疾病，给受影响的农场造成重大的动物痛苦和严重的经济损失。OPA于1825年在南非首次被描述。近200年过去了，我们仍然不知道如何预防这种疾病，甚至不知道如何在早期阶段可靠地诊断它。这是因为在癌症生长的几个月里，感染是沉默的；只有当肿瘤变得足够大，以至于限制呼吸时，感染才会变得明显。重要的是，绵羊对JSRV没有免疫力，我们不能用抗体的存在来诊断感染。需要更多的研究来增加关于JSRV和绵羊肺相互作用的知识，以及这种相互作用如何导致癌症。我们相信，更详细地了解这一过程将提供信息，可用于开发新的诊断测试或疫苗，以控制疾病在养殖绵羊中的传播。因此，本研究项目的目的是增加我们对JSRV引起OPA的机制的了解。该项目有3个主要目标。首先，我们希望确定JSRV感染是如何改变绵羊肺细胞的生理的。我们将通过测量感染肺组织中绵羊基因的活性并与健康肺组织进行比较来实现这一点。其次，我们将检查肺部对JSRV的改良版本的反应，该病毒可以感染绵羊，但不会导致肿瘤。总而言之，前两个实验将产生大量关于哪些基因在感染早期和疾病后期被开启或关闭的信息。我们的第三个目标是更详细地研究少数基因的功能，以确定它们在癌症或阻断JSRV免疫反应中的作用。研究基因的选择将由前两个目标的结果决定。这三个方面的工作将使我们能够剖析出在OPA发展过程中重要的分子变化。这些信息将使我们能够设计控制这种疾病的新战略。更好的疾病控制将提高养羊业的经济可持续性，养羊业正受到OPA等传染病的威胁。反过来，这将通过加强安全、有营养的食品的供应，使农村社区和更广泛的公众受益。重要的是，我们已经进行了一个小规模的项目，表明我们计划的实验方法将带来有价值的结果。在那些初步实验中，我们发现了一些蛋白质，这些蛋白质在癌细胞中比在正常肺中丰富得多。我们目前正在研究其中一些蛋白质在OPA中的作用。计划中的实验将使我们能够在更全面的范围内重复这一过程，这样我们就可以充分了解JSRV与感染绵羊的肺组织的相互作用。此外，OPA有许多不寻常的方面，对这种疾病如何发展的深入了解也将为正常的肺功能提供有价值的信息。因此，该项目的结果也将对研究人类肺部生物学的研究人员产生极大的兴趣。

This proposal concerns a disease in sheep known as ovine pulmonary adenocarcinoma (OPA), which is caused by a virus known as JSRV. JSRV is spread through the air similarly to many other viruses (e.g., flu) and infects cells in the lung where it triggers the growth of cancer. OPA is an important disease affecting sheep flocks in the UK and many other countries, causing significant animal suffering and severe economic losses to affected farms.OPA was first described in South Africa in 1825. Almost 200 years later, we still do not know how to prevent the disease, or even how to reliably diagnose it in the early stages. This is because the infection is silent for many months while the cancer grows; only becoming evident when the tumours become large enough to restrict breathing. Importantly, sheep have no immunity to JSRV and we cannot use the presence of antibodies to diagnose infection. More research is needed to increase knowledge about the interaction of JSRV and the sheep lung, and how that interaction gives rise to cancer. We believe that understanding that process in more detail will provide information that can be used to develop new diagnostic tests or vaccines to control the spread of the disease in farmed sheep.The purpose of this research project is therefore to increase our understanding of the mechanisms by which JSRV causes OPA. The project has 3 main objectives. First, we wish to determine how infection by JSRV alters the physiology of sheep lung cells. We will do this by measuring the activity of sheep genes in infected lung tissue and comparing to that of healthy lungs. Secondly, we will examine how the lungs respond to a modified version of JSRV that can infect sheep but that does not cause tumours. Collectively, these first two experiments will generate a great deal about information on which genes are switched on or off during early infection and during later stages of disease. Our third objective is to study the function of a small number of genes in greater detail to determine their role in cancer or in blocking the immune response to JSRV. The selection of genes for study will be decided by the results from the first two aims.Together, these 3 strands of work will allow us to dissect out the molecular changes that are important in the development of OPA. This information will allow us to design new strategies for controlling this disease. Better disease control will improve the economic sustainability of sheep farming, which is under threat from infectious diseases such as OPA. In turn, this will benefit rural communities and the wider public through strengthening the supply of safe, nutritious food. Importantly, we have already performed a small-scale project that has shown our planned experimental approach will deliver valuable results. In those pilot experiments we identified a number of proteins that are much more abundant in cancer cells than in normal lung. We are currently investigating the role of some of these proteins in OPA. The planned experiments will allow us to repeat this on a more comprehensive scale, so that we fully understand the interaction of JSRV and lung tissue in infected sheep. In addition, there are many unusual aspects to OPA and a deeper understanding of how this disease develops will also provide valuable information on normal lung function. Therefore, the results of this project will also be of great interest to researchers studying lung biology in humans.