Understanding aquaporin-4 relocalisation in the central nervous system

人体大约60%是水，因此，控制我们身体不同部位的含水量对健康至关重要。渗透是水进出细胞的基本过程。活细胞利用水通过水通道蛋白质的流动来控制渗透。这些蛋白质存在于所有生物体的细胞膜中，促进水穿过膜。水通道蛋白-4（AQP 4）是大脑中的水通道蛋白，它在血管和脑组织之间的界面（血脑屏障）富集，并允许水在血液和脑组织之间移动。中风或头部受伤后，这种水运动的控制被破坏，这可能导致水流入大脑。这些多余的水分会导致大脑肿胀并挤压头骨，这可能是致命的或导致长期残疾。在健康的大脑中，水通过AQP 4的运动似乎对某些类型的学习和记忆形成很重要，但原因尚不清楚。我发现AQP 4可以在细胞内部和细胞膜之间移动，并且这个过程在损伤后被激活，导致AQP 4在细胞膜中积累，并增加水通过细胞膜（从而进入脑组织）的速率。使用脊髓损伤和脑损伤的动物模型，我发现阻止AQP 4移动到膜的药物可以减轻肿胀，并大大改善损伤后的恢复。这表明限制AQP 4的膜定位可以帮助创伤和中风患者。这是一种开发通道蛋白药物的全新方法。传统的方法是试图找到一种药物，物理上阻断通道;我的方法是阻止通道到达膜，消除阻断它的必要性。然而，到目前为止，我在实验中使用的药物也阻碍了体内许多其他有用的过程;虽然它们提供了原理证明，但它们在用于患者时也有明显的潜在副作用。在这个项目中，我有两个关键目标。首先是在分子水平上了解AQP 4重新定位到膜的过程。第二个是在实验室中创建一个人类血脑屏障的真实模型，以允许我测试大量药物的方式（这被称为“高通量筛选”方法）。实现这些目标将使我能够开始寻找新的、特异性的药物和药物靶点，这些药物和药物靶点仅限制AQP 4的膜定位，目标是特异性抑制AQP 4的再定位，以治疗脑损伤、脊髓损伤和中风患者，并了解AQP 4在大脑健康功能中的作用。

The human body is approximately 60% water, as such, control of the water content of different parts of our body is vital for health. Osmosis is the fundamental process by which water moves into and out of cells. Living cells control osmosis using the flow of water through aquaporin water channel proteins. These proteins exist in the cell membranes of all living organisms, facilitating the passage of water across the membrane. Aquaporin-4 (AQP4) is the water channel protein in the brain, where it is enriched at the interface between blood vessels and brain tissue (the blood-brain barrier), and allows water to move between the blood and the brain tissue. Following stroke or head injury, control of this water movement is disrupted, which can lead to influx of water into the brain. This excess water causes the brain to swell and press against the skull, which can be fatal or lead to long-term disability. In healthy brains, the movement of water through AQP4 appears to be important for some kinds of learning and memory formation, but it is not understood why. I have discovered that AQP4 can move between the inside of cells and the membrane, and that this process is activated following injury, leading to accumulation of AQP4 in the membrane and increasing the rate at which water can pass through the membrane (and thereby into the brain tissue). Using animal models of spinal cord injury and brain injury, I have found that drugs that stop AQP4 from moving to the membrane can reduce swelling and lead to greatly improved post-injury recovery. This suggests that limiting membrane localisation of AQP4 could help trauma and stroke patients. This is a completely new approach to developing drugs for channel proteins. The traditional approach is to try to find a drug that physically blocks the channel; my approach is to prevent the channel from getting to the membrane, removing the necessity to block it at all. However, the drugs I have used in my experiments so far also block lots of other useful processes in the body; whilst they provide proof-of-principle, they also have obvious potential for unwanted side-effects when used in patients.In this project I have two key goals. The first is to understand, at the molecular level, the process of AQP4 relocalisation to the membrane. The second is to create a realistic model of the human blood brain barrier in the lab, in a way that allows me to test a large number of drugs (this is known as a 'high-throughput screening' approach). Achieving these objectives will put me in a position to begin the search for new, specific drugs and drug targets that ONLY limit membrane localisation of AQP4, with the goal of specific inhibition of AQP4 relocalisation, to treat brain injury, spinal cord injury, and stroke patients, and to understand the role of AQP4 in the healthy functioning of the brain.