Dissecting the pathogenesis of ovine pulmonary adenocarcinoma with RNA-Seq

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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.