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

氧化应激诱导神经系统突触生长的调节 - 遗传和细胞机制的剖析。

基本信息

批准号：
BB/I012273/1
负责人：
Sean Sweeney
金额：
$ 19.6万
依托单位：
University of York
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2011
资助国家：
英国
起止时间：
2011 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FI012273%2F1
关键词：
Oxidative stress induced regulation synaptic

项目摘要

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.

大脑对衰老非常敏感，我们大多数人都有过年老的亲戚记忆力不佳的经历。大脑需要高水平的食物和氧气来有效运作。通过使用大量的氧气来产生能量，大脑产生了一种副产品。这种副产物是有毒形式的氧，被称为活性氧或ROS。正常情况下，大脑可以科普低水平的ROS，这些ROS是正常代谢的副产品，但随着大脑年龄的增长，自我修复机制变得不那么有效，ROS变得过量。ROS通过自我持续的损伤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。我们将由线粒体产生的ROS称为线粒体ROS（mitochondrial ROS，m-ROS）。衰老的大脑努力清除被ROS破坏的细胞物质。随着废物材料的积累，它还可以产生第二个ROS源，由积累的废物材料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）。随着神经元的老化，这两种ROS来源现在都有助于增加损伤周期。我们发现，当ROS过多时，神经细胞之间的连接（称为突触）会过度生长。通常，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会提高它们的通信效率。因此，当我们预期神经元通讯的效率会下降时，我们却惊讶地发现突触在生长。在这个提议中，我们将研究和揭示神经细胞中对ROS反应导致突触生长的过程。我们已经发现，当ROS存在于大脑中时，神经细胞会激活自我更新的过程，并怀疑这可能会诱导突触生长。我们的目标是确定这是如何发生的。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至关重要。这项工作将帮助我们了解导致衰老大脑神经细胞功能衰竭的机制、事件和分子。这项工作的结果很有可能有助于发现药物和治疗方法，以减轻老龄化的不利影响，从而最终造福于整个社会。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders.

DOI：
10.1091/mbc.e16-09-0674
发表时间：
2017-12-15
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Hebbar S;Khandelwal A;Jayashree R;Hindle SJ;Chiang YN;Yew JY;Sweeney ST;Schwudke D
通讯作者：
Schwudke D

Invertebrate models of lysosomal storage disease: what have we learned so far?

溶酶体贮积病的无脊椎动物模型：到目前为止我们学到了什么？