Investigation of the role of the snoRNA U8 in human health and disease

我们想了解一种罕见的大脑疾病的原因，称为白质脑病伴钙化和囊肿（LCC）。虽然LCC最常影响儿童，但它实际上可以出现在任何年龄，在几年的时间里会引起癫痫、运动和思维方面的问题。患者最终死于疾病，因为目前还没有已知的治疗LCC的方法。LCC这个名字来源于医生在扫描受影响患者的脑部时所看到的变化——白质损伤（“白质脑病”）、钙积聚（以一种特定的模式）和囊肿（脑白质中的“洞”）。由于LCC罕见且不易识别，而且直到最近才有诊断性血液检查，因此受影响的患者有时需要取出一块大脑在显微镜下观察。对这些样本的研究表明，导致LCC的问题涉及到脑血管。我们最近发现了一种叫做SNORD118的遗传物质（我们的DNA）的变化（“突变”），这是导致LCC的原因。SNORD118帮助我们的细胞制造一种不同类型的遗传物质，称为RNA。在LCC中突变的特定RNA片段被称为U8。我们知道U8对于产生蛋白质很重要，也就是对细胞工作至关重要的化学物质。然而，这些基因和化学变化是如何导致脑血管细胞出现问题的，目前尚不清楚。为了提高我们对LCC病因的了解，我们开发了一种特殊的斑马鱼，它具有与LCC患者相似的遗传问题。我们最近的工作表明，这种“动物模型”是研究人类LCC如何发生的一个非常有用的工具，已经为U8的功能提供了新的线索。在这个项目中，我们想做更多的实验，包括用我们的斑马鱼，试图找出为什么U8对保持我们大脑血管健康如此重要，以及U8的工作问题是如何导致LCC疾病的。我们认为，这不仅与LCC未来治疗方法的发展有关，而且与我们对涉及脑血管的更常见疾病（如中风）的理解有关。

We want to understand the cause of a rare disease of the brain called leukoencephalopathy with calcifications and cysts (LCC). Although LCC most often affects children, it can actually present at any age, causing problems with seizures, movement and thinking over a period of several years. Patients eventually die of their illness because there is currently no known treatment for LCC.The name LCC comes from the changes that doctors see when they look at the brain scans of affected patients - white matter damage ('leukoencephalopathy'), calcium accumulation (in a particular pattern), and cysts ('holes' in the brain white matter). Because LCC is rare and poorly recognised, and because no diagnostic blood test has been available until recently, affected patients sometimes have a piece of the brain taken out to be looked at under a microscope. Studies of these samples suggest that the problem causing LCC involves the brain blood vessels. We recently discovered changes ('mutations') in a piece of our genetic material (our DNA) called SNORD118 as the cause of LCC. SNORD118 helps our cells to make a different type of genetic material referred to as RNA. The specific piece of RNA mutated in LCC is called U8. We know that U8 is important for producing proteins i.e. chemicals that are crucial for how our cells work. However, how these genetic and chemical changes lead to a problem in the cells of the brain blood vessels is still not known. To improve our understanding of the cause of LCC, we have developed a special zebrafish with a similar genetic problem as is seen in patients affected with LCC. Our recent work shows that this 'animal model' represents a very useful tool for studying how LCC happens in humans, already providing new clues about the function of U8. In this project we want to do more experiments, including using our zebrafish, to try to find out why U8 is so important for keeping the blood vessels in our brain healthy, and how problems with the working of U8 cause the disease LCC. We think that this could be relevant not only for the development of future treatments in LCC, but also for our understanding of more common diseases involving the brain blood vessels, such as stroke.