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

肝脏疾病目前是英国过早死亡的第三大原因，然而与癌症和心脏病不同，肝脏疾病的病例持续上升，肝脏信托基金会估计，超过五分之一的人有患肝脏疾病的风险。因严重肝病入院的患者死亡的可能性是中风或心脏病患者的7-8倍。造成这些惊人数字的两个主要原因是，首先，目前的诊断工具没有发现肝脏疾病的早期迹象，其次，大多数晚期肝病患者没有获得许可的治疗方法。最终，对许多患者来说，这意味着太少、太迟。如果肝脏受损，它可以再生，但如果这种损伤不能停止，肝脏就会留下疤痕。疤痕，也称为纤维化，可导致肝硬化，纤维化和肝硬化的人可能完全没有症状，直到这个过程导致肝功能衰竭和肝癌。纤维化最常见的原因是非酒精性脂肪性肝病（与肥胖和糖尿病相关）、过度饮酒和病毒感染。我们还没有开发出有效的治疗方法来对抗肝纤维化的原因之一是，我们对它是如何开始以及如何恶化的还不够了解。我们的研究将着眼于扭转局面，通过研究肝血管纤维化开始的方式来解决这些重要的临床挑战。血管是我们的运输系统，将氧气和营养物质输送到我们身体的每一个组织。血管并不都是一样的（动脉、静脉和毛细血管），它们在身体的不同部位，甚至在同一个器官中都有非常特殊的作用。确保肝脏血管正常运作，而不是像肾脏血管那样，对身体每个器官的健康和福祉至关重要。维持这些不同的身份被称为血管模式。我们的研究发现，肝脏的血管模式在肝损伤的早期阶段发生了巨大的变化，如果不加以控制，可能直接导致肝纤维化。血管模式的变化是因为排列在所有血管上的细胞——内皮细胞，无法维持其“血管身份”，并经历了一个被称为内皮到间充质转化（简称EndMT）的过程，产生了形成疤痕组织的细胞。令我们兴奋的是，EndMT的过程不仅发生在肝脏疾病期间，而且它有可能逆转，使患病的血管恢复健康。因此，我们将研究1)为什么有些血管接受了EndMT，而另一些血管没有；2)这些细胞是否可以在肝脏症状出现之前预测肝纤维化的发生（当它可能为时已晚而无法治疗时）；3)我们是否可以利用这些知识来生产停止或逆转肝纤维化的新药？为了做到这一点，我们设计了一些实验来观察不同类型的血管在肝纤维化过程中的反应。我们已经发现，被称为非典型趋化因子受体（ACKRs）的特定蛋白质的水平对健康细胞和终末mt细胞的身份及其功能都至关重要。肝纤维化是一个复杂的过程，很难在细胞培养和培养皿中重建。如果没有肝组织，人类疾病很难进行研究，而肝组织很难从病人身上获得，所以我们必须用动物来进行这项研究。我们将使用基因去除ackr的小鼠来了解当它们不存在时肝脏中的血管模式是如何变化的。我们将测试我们是否能开发出新的策略，使用基因疗法来靶向这些传感蛋白，以确定这是否有一天能导致用于治疗纤维化肝病患者的新药。

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.