Oxidative stress induced regulation of synaptic growth in the nervous system - dissection of genetic and cellular mechanisms.

大脑对衰老非常敏感，我们大多数人都有过这样的经历：上了年纪的亲戚记忆力不好。大脑需要大量的食物和氧气才能有效运作。通过使用大量的氧气来产生能量，大脑产生了一种副产品。这种副产物是氧的有毒形式，被称为活性氧或ROS。正常情况下，大脑可以应对作为正常代谢副产物的低水平ROS，但随着大脑年龄的增长，自我修复机制变得不那么有效，ROS变得过多。活性氧通过一种自我延续的损伤循环对细胞具有破坏性。ROS的产生主要发生在细胞内负责从食物和氧气中产生能量的结构线粒体中。我们将线粒体产生的ROS称为线粒体ROS （m-ROS）。衰老的大脑努力清除被活性氧损伤的细胞物质。随着废物的积累，它还可以产生第二个ROS来源，即积累的废物中的金属与氧气反应产生更多的ROS。我们称这些细胞质ROS （c-ROS）。随着神经元年龄的增长，这两种ROS的来源都有助于增加损伤周期。我们发现，当活性氧过量时，神经细胞之间的连接，即突触，会过度生长。众所周知，当大脑执行学习和记忆功能时，突触会生长，神经细胞之间的连接提高了它们的交流效率。因此，当我们预期神经元交流的效率会下降时，突触却在生长，这让我们感到惊讶。在本提案中，我们将研究并揭示神经细胞中对活性氧反应导致突触生长的过程。我们已经发现，当活性氧存在于大脑中时，神经细胞会激活一个自我更新的过程，并怀疑这可能是诱导突触生长的原因。我们的目标是确定这究竟是如何发生的。我们观察到的变化很可能对我们理解随着年龄的增长大脑功能的衰退具有至关重要的意义。这项工作将帮助我们了解导致大脑衰老中神经细胞功能衰竭的机制、事件和分子。这项工作的结果完全有可能帮助发现减轻衰老不利影响的药物和治疗方法，从而最终使整个社会受益。

Brains are very sensitive to ageing and most of us have experience of ageing relatives with faulty memories. The brain requires high levels of food and oxygen to function effectively. By using a lot of oxygen to generate energy, the brain produces a by-product. This by-product is toxic forms of oxygen and is termed Reactive Oxygen Species or ROS. Normally the brain can cope with low levels of ROS that are generated as a by-product of normal metabolism, but as the brain ages, the self-repair mechanisms become less effective and ROS become excessive. ROS are destructive to cells by a self-perpetuating cycle of damage. Primarily, ROS generation occurs in the structure within the cell responsible for producing energy from food and oxygen called the mitochondria. We term ROS generated by the mitochondria, mitochondrial ROS (m-ROS). An ageing brain struggles to clear itself of cellular material damaged by ROS. As waste material accumulates, it can also generate a second source of ROS, generated by metals within the accumulated waste material reacting with oxygen to produce more ROS. We term these cytoplasmic ROS (c-ROS). Both sources of ROS now contribute to the increasing cycle of damage as neurons age. We found that the connections between nerve cells, called synapses, grow excessively when ROS are excessive. Synapses are normally known to grow while the brain carries out learning and memory functions and the connections between nerve cells improve their communication efficiency. We therefore find it surprising to see synapses growing during a period when we would expect a decline in the efficiency of neuronal communication. In this proposal we will examine and uncover the processes in nerve cells that react to ROS to cause synapse growth. We have already found that nerve cells activate a process of self-renewal when ROS are present in the brain and suspect that this may be inducing synapse growth. Exactly how this happens we aim to determine. The changes that we have observed are very likely of critical importance to our understanding of the decline in brain function as we age. This work will help us to understand the mechanisms, events and molecules that cause failure in nerve cell function in the ageing brain. The results of this work have every potential to aid the discovery of drugs and treatments to alleviate adverse effects of ageing and will thus, in time, benefit society as a whole.