Spatio-temporal imaging of calcium in degenerating nerves

退化神经中钙的时空成像

• 批准号: BB/D005159/1
• 负责人: Michael Philip Coleman
• 金额: $ 32.38万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD005159%2F1
• 关键词: Spatio; temporal; imaging; calcium; degenerating

Axons are the long processes that link neurons together within our brain, spinal cord and peripheral nervous system, allowing neurons to communicate rapidly with one another. They are huge structures, up to 1 metre long in man, making human motor neurons, for example, the largest single cell within the human body. Naturally with such huge structures, there are significant logistical problems in maintaining axons. Failure to do so is the cause of a number of human neurological disorders, not only those where there is direct axonal injury such as spinal injury, but also many where the disorder is inherited such as motor neuron disease, or acquired such as exposure to neurotoxins. We are beginning to understand that the way in which axons die is similar in each of these seemingly unrelated circumstances. However, we do not yet fully understand what that mechanism is. Inorganic ions such as sodium and potassium play important roles in the transmission of the action potential, the means by which information passes rapidly along an axon from one end to another. However, another inorganic ion, calcium, plays a rather different but equally critical role in axons. Calcium is normally pumped out of all cells, including neurons, because high levels of calcium inside the cell are extremely dangerous. It is also pumped into specific stores within cells, including inside the axon, from where it may be released and used to signal certain events and processes so that the cell or axon can respond accordingly. We have some preliminary data suggesting that release of calcium from such stores occurs after an axon is injured, but long before the axon actually degenerates. When we repeated these experiments in the presence of a genetic mutation that protects injured axons from degenerating, the redistribution of calcium was also blocked. The possible causative link between these two events needs to be established by appropriate experiments. For example, if calcium release from the internal stores is part of the signalling mechanism that causes the axon to degenerate, then one would expect that causing calcium to be released from intracellular stores by another method (e.g., by adding an appropriate drug) would have a similar effect. We will carry out a series of experiments to test for such a causative link, and if we find it, to determine how it might be exploited. In the short term our aim is to understand better fundamental mechanisms of axon death. This is a very important issue because axons make up by far the largest part of most neurons and because they are essential for the function of that neuron and for the most part cannot be replaced if they are lost. In the longer term, understanding this process should lead to new ways to treat, or even prevent, a wide spectrum of neurodegenerative conditions.

轴突是将我们的大脑，脊髓和外周神经系统中的神经元连接在一起的长过程，允许神经元快速相互交流。它们是巨大的结构，在人体内长达1米，使人类运动神经元成为人体内最大的单细胞。当然，对于如此巨大的结构，在维持轴突方面存在重大的后勤问题。不这样做是许多人类神经系统疾病的原因，不仅是那些存在直接轴突损伤如脊髓损伤的疾病，而且还有许多疾病是遗传性的，如运动神经元疾病，或获得性的，如暴露于神经毒素。我们开始了解，在这些看似无关的情况下，轴突死亡的方式是相似的。然而，我们还不完全理解这一机制是什么。无机离子如钠和钾在动作电位的传递中起着重要的作用，动作电位是信息沿着轴突从一端沿着迅速传递到另一端的手段。然而，另一种无机离子钙在轴突中起着相当不同但同样重要的作用。钙通常被泵出所有细胞，包括神经元，因为细胞内高水平的钙是非常危险的。它还被泵入细胞内的特定储存，包括轴突内部，从那里它可以被释放并用于发出某些事件和过程的信号，以便细胞或轴突可以相应地做出反应。我们有一些初步的数据表明，在轴突受伤后，从这些储存中释放出的钙会发生，但远在轴突真正退化之前。当我们在存在保护受损轴突免于退化的基因突变的情况下重复这些实验时，钙的再分布也被阻断了。这两个事件之间可能的因果关系需要通过适当的实验来确定。例如，如果从内部储存释放钙是导致轴突退化的信号传导机制的一部分，那么可以预期通过另一种方法（例如，通过添加适当的药物）将具有类似的效果。我们将进行一系列的实验来测试这种因果关系，如果我们找到了它，以确定如何利用它。在短期内，我们的目标是更好地了解轴突死亡的基本机制。这是一个非常重要的问题，因为轴突构成了大多数神经元的最大部分，并且因为它们对于该神经元的功能至关重要，并且如果它们丢失，在大多数情况下无法被替换。从长远来看，了解这一过程应该会导致治疗甚至预防各种神经退行性疾病的新方法。