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亲戚年迈、记忆力不佳的经历。大脑需要高水平的食物和氧气才能有效运作。通过使用大量氧气来产生能量，大脑会产生一种副产品。这种副产物是有毒形式的氧，被称为活性氧物种或ROS。正常情况下，大脑可以应对正常新陈代谢产生的低水平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。ROS通过自我延续的损害循环对细胞具有破坏性。首先，ROS的产生发生在细胞内负责从食物和氧气中产生能量的结构中，称为线粒体。我们将线粒体产生的ROS称为线粒体ROS(m-ROS)。老化的大脑努力清除被ROS破坏的细胞物质。随着废物的积累，它还可以产生第二种来源的ROS，由积累的废物中的金属与氧气反应产生更多的ROS。我们称之为细胞质ROS(c-ROS)。随着神经元的老化，这两种ROS来源现在都会导致损伤周期的增加。我们发现，当ROS过多时，神经细胞之间的连接，即突触，会过度增长。突触通常被认为是在大脑进行学习和记忆功能时生长的，神经细胞之间的连接提高了它们的通信效率。因此，我们感到惊讶的是，在我们预计神经元交流效率会下降的时期，突触却在增长。在这项提案中，我们将检查并揭示神经细胞中与ROS反应导致突触生长的过程。我们已经发现，当大脑中存在ROS时，神经细胞会激活自我更新的过程，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种情况到底是如何发生的。我们观察到的变化很可能对我们理解大脑功能随着年龄的增长而下降具有至关重要的意义。这项工作将帮助我们了解导致老化大脑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老龄化不利影响的药物和治疗方法，从而最终造福于整个社会。

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.