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

非典型趋化因子受体通过内皮-间质转化协调纤维化肝病期间血管模式的变化。

• 批准号: MR/Y013751/1
• 负责人: NEIL DUFTON
• 金额: $ 77.77万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY013751%2F1
• 关键词: Atypical; Chemokine; Receptors; orchestrate; changes

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.

目前，在英国，肝脏疾病是导致过早死亡的第三大主要原因，然而，与癌症和心脏病不同的是，肝脏疾病的病例正在继续上升，据肝脏信托基金估计，超过五分之一的人面临发展为肝脏疾病的风险。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，第一，目前的诊断工具没有发现肝病的早期迹象，第二，大多数晚期肝病患者没有获得许可的治疗方法。最终，这对许多患者来说意味着太少、太迟。如果肝脏受损，肝脏可以再生，但如果这种损伤不停止，肝脏就会伤痕累累。疤痕形成，也称为纤维化，可导致肝硬变，患有纤维化和肝硬变的人可能完全好，没有任何症状，直到这个过程导致肝功能衰竭和肝癌。最常见的纤维化原因是非酒精性脂肪性肝病(与肥胖和糖尿病有关)、过度饮酒和病毒感染。我们没有开发有效的治疗方法来对抗肝纤维化的原因之一是，我们仍然不够清楚它是如何开始的，以及它是如何恶化的。我们的研究将寻求扭转局面，并通过研究肝血管纤维化的开始方式来解决这些重要的临床挑战。血管是我们的运输系统，向我们体内的每一个组织输送氧气和营养。血管并不都是一样的(动脉、静脉和毛细血管)，在身体的不同部位，甚至在同一器官中都有非常特殊的作用。确保肝血管按其应有的方式运作，而不是像肾血管那样运作，对于身体每个器官的健康和福祉至关重要。保持这些不同的身份被称为血管图案化。我们的研究发现，肝脏的血管模式在肝损伤的非常早期阶段就会发生巨大的变化，如果不加以控制，可能会直接导致肝纤维化。血管构型的变化是因为排列在所有血管上的细胞--内皮细胞--无法保持其‘血管特性’，并经历一种称为内皮-间充质转变(简称EndMT)的过程，从而产生形成疤痕组织的细胞。EndMT的过程令我们兴奋的不仅是它发生在肝脏疾病期间，而且它有可能被逆转，将患病的血管重新变成健康的血管。因此，我们将调查1)为什么一些血管接受EndMT，而其他血管不接受EndMT；2)这些细胞是否可以在肝症状出现之前预测肝纤维化发生(当治疗可能为时已晚)3)我们能否利用这一知识生产阻止或逆转肝纤维化的新药？为此，我们设计了实验，观察不同类型的血管在肝纤维化期间的反应。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和EndMT细胞的身份及其功能都是至关重要的。肝纤维化是一个复杂的过程，很难在细胞培养和培养皿中复制。没有肝组织，人类疾病的研究可能非常困难，而肝组织很难从患者那里获得，因此我们不得不使用动物进行这项研究。我们将使用ACKR基因移除的小鼠来了解当它们不存在时，肝脏中的血管图案是如何变化的。我们将测试是否可以开发新的策略，使用基因疗法来靶向这些传感蛋白，以确定这是否有一天会导致新的药物可用于治疗纤维性肝病患者。