Neuronal vulnerability to ischaemia: the role of AMPA receptor trafficking.

本研究的目的是确定脑损伤（如中风或其他神经系统疾病）后导致脑神经细胞功能障碍或死亡的机制。脑缺血发生在脑的一部分血液供应中断时，例如动脉阻塞（中风）或心力衰竭。中风引起的脑损伤对个人、社会和经济都有巨大的影响。据估计，每年有15万人患有中风，使其成为英国第三大常见死因。它也是导致严重残疾的最常见原因之一，超过25万人因这种情况而残疾。大脑中的神经细胞（神经元）需要恒定的血液供应来提供生命所必需的因素，特别是氧气和葡萄糖，如果没有这些因素，神经元就会发生故障并死亡。缺血的一个有趣的方面是，某些大脑区域的神经元比其他区域更容易因缺血性损伤而死亡。这项计划的目的是研究这些差异背后的机制，希望我们从研究中获得的知识可以用来使脆弱的神经元在脑缺血后不太可能死亡。神经元通过称为神经递质的化学物质相互交流，这些化学物质从一个神经元释放出来，通过一个称为突触的间隙被另一个神经元通过特殊的受体接收。在与缺血相关的氧和葡萄糖剥夺（OGD）期间，一种非常重要的神经递质受体（称为AMPA受体）的性质发生变化，使得它允许比平常更多的钙进入神经元。正是这种异常的钙离子进入导致脑缺血后数小时或数天的神经元死亡。我们已经表明，不太脆弱的神经元对OGD的反应是AMPA受体特性的不同改变，这可能导致细胞内钙离子进入减少。我们建议研究AMPA受体在不同类型神经元的OGD过程中如何变化的分子机制，并研究AMPA受体在突触处变化方式的细微差异对神经元死亡的可能性产生深远影响的想法。我们的大多数实验将使用从大鼠大脑中获得的神经元进行。这些神经元可以从大脑中分离出来，然后在培养皿中保持“活力”。我们还将使用保留神经元之间一些重要连接的大鼠大脑切片。使用这些细胞和切片，我们将能够更多地了解神经元中响应OGD的机制。我们将使用药物或基因技术来改变这些机制，看看我们是否可以阻止神经元死亡。已经表明，其他疾病，包括运动神经元疾病和创伤性脑损伤（物理冲击损伤），涉及突触AMPA受体的类似变化。因此，这项工作将提供有关神经元如何对一系列神经系统疾病做出反应的关键信息。

The aim of this research is to define mechanisms that contribute to the dysfunction or death of nerve cells in the brain following brain injury, such as a stroke, or other neurological disorders.Brain ischaemia occurs when the blood supply to a part of the brain is interrupted, for example by blockage of an artery (a stroke) or by heart failure. Brain damage caused by stroke has huge personal, social and economic impact. An estimated 150,000 people per year suffer from a stroke, making it the third most common cause of death in the UK. It is also one of the most common causes of severe disability, and more than 250,000 people live with disabilities caused by this condition. Nerve cells (neurons) in the brain need a constant blood supply to provide essential factors for life, especially oxygen and glucose, and without these factors, neurons malfunction and die. An intriguing aspect of ischaemia is that neurons in certain brain regions are more likely to die as a result of an ischaemic injury than others. The aim of this proposal is to investigate the mechanisms that underlie these differences, with the hope that the knowledge we gain from our research could be used to make vulnerable neurons less likely to die following brain ischaemia.Neurons communicate with each other via chemicals known as neurotransmitters, which are released from one neuron to be received by another via special receptors across a gap called a synapse. During the oxygen and glucose deprivation (OGD) associated with ischaemia, the properties of a very important type of neurotransmitter receptor (called the AMPA receptor), change in such a way that it allows more calcium than usual to enter neurons. It is this abnormal calcium entry that leads to neuronal death hours or days after brain ischaemia.We have shown that less vulnerable neurons respond to OGD with different alterations of AMPA receptor properties, which are likely to result in reduced calcium entry into the cell. We propose to study the molecular mechanisms that underlie how AMPA receptors change during OGD in the different types of neurons, and investigate the idea that subtle differences in the way AMPA receptors change at synapses has a profound influence on the likelihood that the neurons will die. Most of our experiments will be carried out using neurons obtained from the rat brain. These neurons can be isolated from the brain and then kept 'alive' in a petri dish. We will also use slices of rat brain that keep some of the important connections between neurons. Using these cells and slices we will be able to understand more about the mechanisms that occur in response to OGD in neurons. We will then modify these mechanisms using drugs or genetic techniques to see if we can stop neurons from dying.It has been shown that other disorders, including motor neuron disease and traumatic brain injury (physical impact injury), involve similar changes in AMPA receptors at synapses. This work will therefore provide crucial information about how neurons respond to a range of neurological disorders.