Modulating cholesterol 25-hydroxylase: a strategy to accelerate haematoma clearance after intracerebral haemorrhage to improve outcome

中风是一种危及生命的疾病，它会导致脑部血液供应中断。出血性中风是最致命的中风类型，死亡率为50%，那些存活下来的人通常会留下影响日常生活的改变生活的损伤。中风的长期影响包括运动和平衡困难，沟通、记忆、注意力、视力和吞咽问题，以及极度疲劳。目前，出血性中风没有有效的治疗方案，因此迫切需要找到新的治疗方法来改善患者的生存和生活质量。出血性中风的一种类型（“脑出血”）发生在血管突然破裂并开始出血进入大脑时。血液在大脑内积聚，导致压力升高，导致脑细胞死亡。现在大脑中的血液中含有各种细胞（包括红细胞），这些细胞开始释放“有毒因素”，从而进一步损害脑细胞。因此，重要的是要尽可能快地排出血液，以减少它造成任何伤害的机会。我们的组织/器官包含一组被称为“吞噬细胞”的细胞，它们的工作是吃掉任何有害细胞和更小的颗粒，以保护我们的身体免受任何有害影响。在出血性中风中，这些“吞噬细胞”试图吃掉红血球和有毒因子。然而，这项工作需要时间，试图找到一种方法来帮助吞噬细胞更快、更有效地清除血液，将有助于防止对大脑的进一步损害。我们发现，在出血后，吞噬细胞中一种叫做“胆固醇25-羟化酶”（Ch25h）的蛋白质的含量会上升，我们相信这种蛋白质可能有助于吞噬细胞更好地清除血液。在这个应用程序中，我们将汇集一个独特的科学家团队，他们将使用脑出血动物模型以及死于这种情况的患者的组织来了解更多关于Ch25h在大脑中的作用。我们将尝试弄清楚Ch25h是否能帮助吞噬细胞清除血液。正常情况下，在细胞中，Ch25h刺激其他分子的产生和释放，包括25-羟基胆固醇（25-HC）。因此，我们将给有脑出血的动物注射25-HC，并测试它是否能提高血液从大脑中排出的程度，以及它是否也能改善这种中风的症状。通过这项工作，我们希望找到一种潜在的新方法来改善结果并减少出血性中风的负面影响，出血性中风是一种危及生命的疾病，目前尚无治疗方案。

Stroke is a life-threatening condition in which there is a disruption of blood supply to the brain. Haemorrhagic stroke is the deadliest type of stroke leading to a 50% chance of death, and those who survive are usually left with life-changing impairments that affect everyday living. The longer-term effects of stroke include difficulties with movement and balance, and problems with communication, remembering things, concentration, vision and swallowing as well as extreme fatigue. Currently there are no effective treatment options for haemorrhagic stroke so there is an urgent need to find new therapies to improve patient survival and quality of life. One type of haemorrhagic stroke ('intracerebral haemorrhage') occurs when a blood vessel suddenly ruptures and begins bleeding into the brain. Blood then accumulates inside the brain, leading to a rise in pressure that causes brain cells to die. Blood that is now in the brain contains various cells (including red blood cells) that start to release 'toxic factors' that can cause further damage to brain cells. It is important therefore, to try and get rid of the blood as quickly as possible, to reduce the chances of it causing any harm. Our tissues/organs contain a group of cells called 'phagocytes' whose job is to eat any harmful cells and smaller particles to try to protect our bodies from any of their harmful effects. In haemorrhagic stroke, these 'phagocytes' try to eat up the red blood cells and toxic factors. However, this job can take time and trying to find a way to help the phagocytes get rid of the blood quicker and more efficiently would help to prevent further damage to the brain. We have discovered that the amount of a protein called 'cholesterol 25-hydroxylase' (Ch25h) goes up in the phagocytes after haemorrhage, and we believe that this protein might help the phagocytes to work better to clear away the blood. In this application we will bring together a unique team of scientists who will use animal models of brain haemorrhage as well as tissue from patients who died from this condition to learn more about what Ch25h is doing in the brain. We will try to work out if Ch25h can help the phagocytes to remove blood. Normally in cells, Ch25h stimulates the production and release of other molecules including 25-hydroxycholesterol (25-HC). We will therefore give 25-HC to animals that have brain haemorrhage and test if this increases how well the blood is removed from the brain, and if it can also improve the symptoms seen in this type of stroke. By doing this work, we hope to identify a potential new way to improve outcome and reduce the negative impact of haemorrhagic stroke, a life-threatening condition with no current treatment options.