权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Harnessing natural cellular variability to understand how neurons maintain their axodendritic polarity

利用自然细胞变异性来了解神经元如何维持其轴突极性

基本信息

批准号：
BB/V000195/1
负责人：
Matthew Grubb
金额：
$ 70.01万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV000195%2F1
关键词：
Harnessing natural cellular variability understand

项目摘要

The different parts of your body all play different roles in keeping you alive and healthy. But dividing jobs between different spatial compartments like this doesn't just happen at the level of the whole organism - many of your individual cells do this too. This phenomenon of compartmentalising functions within distinct sub-cellular zones is known as 'polarity', and it reaches its peak in your brain cells, or neurons. Most neurons are broadly divided into two major polar specialisations: dendrites and axons. These have distinct structural and functional attributes that are crucial for information flow within neuronal circuits. Understanding how individual neurons organise themselves into axons and dendrites is therefore vital for understanding how a healthy brain operates. However, while we know a good amount about the processes involved in setting up neuronal polarity in the first place, we currently know a lot less about how neurons keep their polarity intact afterwards. How do neurons make sure that their axons stay axons, and their dendrites stay dendrites? Given that your brain cells are normally about as old as you are, maintaining polarity like this is a process that must operate successfully over decades. On the other hand, any deficits in polarity maintenance have the potential to fundamentally disrupt brain function.For these reasons, the goal of our proposal is to discover novel mechanisms that neurons use to maintain their polarity. We will do this by taking advantage of a unique case of natural variability. Whilst almost all mature neurons in the mammalian brain possess one, and only one axon, our laboratory has recently identified a population of cells that is very different. In the olfactory bulb, the first region of the brain to process information about the sense of smell, there is a set of neurons that naturally come in different polarity types. Some of these dopamine-releasing neurons possess an axon, but others lack an axon entirely. We will exploit this natural heterogeneity by using cutting-edge technology to compare and manipulate these different sub-types of dopaminergic cell at the molecular level. In doing so, we will ask which mechanisms are crucial for maintaining axons as axons and which are vital for maintaining dendrites as dendrites.By addressing these important basic biological questions, our proposal has the potential to positively impact future healthcare in the UK. Our study of the olfactory system could benefit future approaches to treat debilitating smell disorders such as anosmia and hyposmia, which affect at least 20% of the population and have a significant impact on quality of life. Our focus on dopaminergic neurons may inform treatments for disorders where these cells are lost in later life, such as Parkinson's Disease. Finally, any new knowledge we generate about ways to maintain the identity of neuronal compartments could prove crucial in therapeutic efforts to repair damage after brain injury or neurodegenerative disease.

你身体的不同部位在保持你的健康和活力方面发挥着不同的作用。但是，像这样在不同的空间隔间之间分配工作并不仅仅发生在整个生物体的水平上-你的许多个体细胞也会这样做。这种在不同的亚细胞区域内划分功能的现象被称为“极性”，它在你的脑细胞或神经元中达到顶峰。大多数神经元大致分为两个主要的极性特化：树突和轴突。它们具有独特的结构和功能属性，对于神经元回路内的信息流至关重要。因此，了解单个神经元如何组织成轴突和树突对于了解健康的大脑如何运作至关重要。然而，尽管我们首先对建立神经元极性的过程有了很好的了解，但我们目前对神经元如何保持其极性的完整性知之甚少。神经元如何确保它们的轴突保持轴突，树突保持树突？考虑到你的脑细胞通常和你一样老，保持这样的极性是一个必须在几十年内成功运作的过程。另一方面，极性维持的任何缺陷都有可能从根本上破坏大脑功能。出于这些原因，我们的目标是发现神经元用于维持其极性的新机制。我们将通过利用自然变异的独特情况来做到这一点。虽然哺乳动物大脑中几乎所有的成熟神经元都有一个，而且只有一个轴突，但我们的实验室最近发现了一群非常不同的细胞。嗅球是大脑中处理嗅觉信息的第一个区域，在嗅球中有一组神经元，它们自然地具有不同的极性类型。这些释放多巴胺的神经元中的一些具有轴突，但另一些则完全缺乏轴突。我们将利用这种天然的异质性，通过使用尖端技术在分子水平上比较和操纵这些不同的多巴胺能细胞亚型。在这样做的时候，我们将问哪些机制是至关重要的维持轴突作为轴突，哪些是至关重要的维持树突作为dendrites.By解决这些重要的基本生物学问题，我们的建议有可能积极影响未来的医疗保健在英国。我们对嗅觉系统的研究可能有助于未来治疗嗅觉障碍（如嗅觉缺失和嗅觉减退）的方法，这些疾病影响至少20%的人口，并对生活质量产生重大影响。我们对多巴胺能神经元的关注可能会为这些细胞在晚年丢失的疾病（如帕金森病）的治疗提供信息。最后，我们产生的关于维持神经元区室身份的方法的任何新知识都可能在脑损伤或神经退行性疾病后修复损伤的治疗努力中至关重要。