Atypical Chemokine Receptors orchestrate changes in vascular patterning during fibrotic liver disease via Endothelial-to-Mesenchymal Transition.

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Liver disease is currently the 3rd major cause of premature death in the UK, however unlike cancer and heart disease, cases of liver disease are continuing to rise with the Liver Trust estimating that more than 1 in 5 of us are at risk of developing liver disease. Patients admitted to hospital with severe liver disease are 7-8 times more likely to die than patients having a stroke or heart attack. The two main reasons for these stark numbers are, firstly, early signs of liver disease are missed by current diagnostic tools, and secondly, there are no licenced treatments for most people who have advanced liver disease. Ultimately this means too little too late for many patients.The liver can regenerate if damaged but if that damage doesn't stop then the liver becomes scarred. Scarring, also called fibrosis, can lead to cirrhosis and people with fibrosis and cirrhosis may be entirely well with no symptoms until the process leads to liver failure and liver cancer. The most common causes of fibrosis are non-alcoholic fatty liver disease (associated with obesity and diabetes), excessive alcohol use and viral infection. One of the reasons why we have not developed effective treatments to combat liver fibrosis is because we still do not know enough about how it starts and how it gets worse. Our research will look to turn the tables in our favour and address these important clinical challenges by studying the way in which fibrosis begins in the liver's blood vessels.Blood vessels are our transport system delivering oxygen and nutrients to every tissue in our body. Blood vessels are not all the same (arteries, veins and capillaries) and have very specialised roles in different parts of the body and even in the same organ. Making sure that a liver blood vessel behaves as it should and not, for example, like a kidney blood vessel is crucial for the health and well-being of each organ of the body. Maintaining these distinct identities is referred to as vascular patterning. Our research has found that the vascular patterning of the liver changes dramatically at very early stages of liver injury and, if unchecked, can lead directly to liver fibrosis. The changes in vascular patterning occur because the cells that line all blood vessels, endothelial cells, are unable to maintain their 'vascular identity' and undergo a process known as Endothelial-to-Mesenchymal Transition (EndMT for short) producing cells that make scar tissue. What excites us about the process of EndMT is not only that it happens during liver disease but the fact that it has the potential to be reversed and change diseased blood vessels back to healthy ones. Therefore, we will investigate 1) why some blood vessels undergo EndMT but others do not 2) Whether these cells can be used to predict liver fibrosis occurring before liver symptoms occur (when it might be too late to treat) 3) Can we use this knowledge to produce new drugs that stop or reverse liver fibrosis?To do this, we have designed experiments that will see how different types of blood vessel respond during liver fibrosis. We have discovered that the levels of particular proteins called atypical chemokine receptors (ACKRs) are crucial to both the identity of healthy and EndMT cells and what they do. Liver fibrosis is a complex process which is difficult to recreate in cell cultures and petri dishes. Human disease can be very difficult to study without liver tissue which is difficult to obtain from patients and so we have to use animals for this research. We will use mice that have had ACKRs genetically removed to understand how vascular patterning changes in the liver when they do not exist. We are going to test if we can develop new strategies to target these sensing proteins using gene therapy to determine if this could one day lead to new drugs that can be used to treat patients with fibrotic liver disease.