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Mechanisms and consequences of presynaptic protein SUMOylation in the regulation of neurotransmitter release

突触前蛋白 SUMO 化调节神经递质释放的机制和后果

基本信息

批准号：
BB/K014358/1
负责人：
Jeremy Henley
金额：
$ 50.72万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FK014358%2F1
关键词：
Mechanisms consequences presynaptic protein SUMOylation

项目摘要

The human brain is widely considered to be the most complex structure in the known universe. Despite this massive complexity, remarkable progress has been achieved towards understanding individual cells of the brain, how they communicate and how this communication is modified by development, experience, aging and disease. The brain is composed of neurons, which pass chemical signals to each other via specialised structures called synapses. Synapses are highly plastic and constantly undergo changes in the efficiency of information transfer. It is these changes in plasticity that underlie learning, memory and cognition. On the other hand, detrimental changes in synapses are responsible for many brain diseases including age-associated cognitive decline and dementia. Synapses are composed of three basic components: the presynaptic terminal, which is activated by an electrical signal and converts this to a chemical signal by releasing a chemical (neurotransmitter) from the specialised structures called vesicles; the synaptic cleft, across which the neurotransmitter diffuses; and the postsynaptic membrane, which contains receptor proteins that detect the neurotransmitter and convert the chemical signal back to an electrical signal. This project seeks to better understand the processes of neurotransmitter release at the presynaptic terminal. More specifically we are interested in a process called SUMOylation, in which a small protein, SUMO, is coupled to another 'target' protein to alter its function. We have already shown that protein SUMOylation at the presynaptic terminal affects the amount of neurotransmitter release. In this study we want to explore exactly which SUMOylated proteins cause these changes in release and how these changes are coordinated to tune synaptic function. We intend to focus on three proteins that are already well established as fundamental components of the neurotransmitter release process. Importantly, we have validated that they are modified by SUMO but the effects are entirely unknown.We believe that our work is new, exciting and important because it directly addresses questions about how synapses operate. Increased understanding of the processes that control neurotransmitter release in normal healthy cells will also provide valuable information for what can go wrong, and potentially how to fix it, in aging and diseased synapses.

人脑被广泛认为是已知宇宙中最复杂的结构。尽管如此巨大的复杂性，在理解大脑的单个细胞，它们如何交流以及这种交流如何被发育，经验，衰老和疾病所改变方面已经取得了显着的进展。大脑由神经元组成，神经元通过称为突触的专门结构相互传递化学信号。突触具有高度可塑性，并且在信息传递的效率上不断发生变化。正是这些可塑性的变化构成了学习、记忆和认知的基础。另一方面，突触的有害变化是许多脑部疾病的原因，包括与年龄相关的认知能力下降和痴呆症。突触由三个基本部分组成：突触前末梢，它被电信号激活，并通过释放化学物质将电信号转化为化学信号。（神经递质）从称为囊泡的专门结构;突触间隙，神经递质扩散;和突触后膜它含有受体蛋白，可以检测神经递质并将化学信号转换回电信号。这个项目旨在更好地了解突触前末梢神经递质释放的过程。更具体地说，我们感兴趣的是一个称为SUMO化的过程，其中一个小蛋白SUMO与另一个“目标”蛋白偶联以改变其功能。我们已经证明突触前末梢的SUMO化影响神经递质的释放量。在这项研究中，我们希望探索到底是哪些SUMO化蛋白引起这些释放变化，以及这些变化如何协调以调节突触功能。我们打算把重点放在三个蛋白质，已经被确定为神经递质释放过程的基本组成部分。重要的是，我们已经证实它们被SUMO修饰，但效果完全未知。我们相信我们的工作是新的，令人兴奋的和重要的，因为它直接解决了突触如何运作的问题。对正常健康细胞中控制神经递质释放的过程的进一步了解也将为衰老和患病突触中可能出现的错误以及如何修复提供有价值的信息。