Transgenic approaches to understanding astrocyte heterogeneity

了解星形胶质细胞异质性的转基因方法

• 批准号: BB/L003236/1
• 负责人: Huiliang Li
• 金额: $ 73.54万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL003236%2F1
• 关键词: Transgenic; approaches; understanding; astrocyte; heterogeneity

The cells in our brain are generally divided into two major categories based on their function - neurons (commonly known as nerve cells) and glial cells. Neurons are very important to our body because they process and transmit information to control our actions in daily life, while glial cells are seen as playing supporting roles to neurons. We used to think that our brain was mainly run by neurons with a little help from glia. In recent years, with rapid advances in neuroscience, this view has started to change and we now recognize that brain function is the result of concerted activities of both neurons and glia. Astrocytes are an important class of glial cells defined by their star-like shape and other features. Despite the fact that they are the most abundant cells in the brain making up half of the brain volume, our knowledge about astrocytes is still rudimentary. Astrocytes are thought to be highly diverse, and our previous work found a link between their diversity and developmental origin - that is, we might be able to predict an astrocyte's function according to where it comes from in early development. Our proposed study aims to explore further how astrocytes diversify during development and after settling in their final resting site in the mature brain, where they come under the influence of micro-environmental signals from neurons and other cells in their vicinity. Based on our data so far, we hypothesize that astrocyte diversity is determined at both developmental and micro-environmental levels. We will test this hypothesis by experiments in mice. Through genetic ("transgenic") manipulation of mice we are able to label different populations of astrocytes with green or red fluorescent proteins and also to perform "genetic surgery" to remove particular astrocyte populations of interest. We aim to produce a map of the developmental origins of astrocyte sub-populations and to relate this to the adult functions of the astrocytes in, for example, supporting communication among neurons. In addition, we plan to identify new molecular markers for the different populations of astrocytes. The reason why we need to study astrocyte development and diversity is that different subtypes of astrocytes might be functionally distinct from each other and therefore differentially involved in brain disorders such as autism. Our proposed study will produce direct information about astrocyte functional diversity and provide useful tools for future astrocyte research that can be provided to the neuroscience community at large.

我们大脑中的细胞通常根据其功能分为两大类-神经元(俗称神经细胞)和神经胶质细胞。神经元对我们的身体非常重要，因为它们处理和传递信息来控制我们在日常生活中的行为，而神经胶质细胞则被视为对神经元起着支持作用。我们曾经认为我们的大脑主要是由神经元控制的，神经胶质细胞提供了一点帮助。近年来，随着神经科学的快速发展，这种观点已经开始改变，我们现在认识到，大脑功能是神经元和胶质细胞协同活动的结果。星形胶质细胞是一类重要的神经胶质细胞，具有星形和其他特征。尽管星形胶质细胞是大脑中最丰富的细胞，占大脑体积的一半，但我们对星形胶质细胞的了解仍然很初级。星形胶质细胞被认为是高度多样化的，我们之前的工作发现了它们的多样性与发育起源之间的联系--也就是说，我们或许能够根据星形胶质细胞在早期发育中的来源来预测它的功能。我们提出的研究旨在进一步探索星形胶质细胞在发育过程中和在成熟大脑中的最终休息位置定居后如何多样化，在那里它们受到来自附近神经元和其他细胞的微环境信号的影响。根据我们到目前为止的数据，我们假设星形胶质细胞的多样性是在发育和微环境水平上决定的。我们将通过在老鼠身上的实验来验证这一假设。通过对小鼠的遗传(“转基因”)操作，我们能够用绿色或红色荧光蛋白标记不同的星形胶质细胞群，也可以执行“基因手术”来移除特定的感兴趣的星形胶质细胞群。我们的目标是绘制星形胶质细胞亚群发育起源的地图，并将其与星形胶质细胞的成年功能联系起来，例如，支持神经元之间的交流。此外，我们计划为不同群体的星形胶质细胞识别新的分子标记。我们之所以需要研究星形胶质细胞的发育和多样性，是因为不同亚型的星形胶质细胞可能在功能上彼此不同，因此与自闭症等脑部疾病的关系不同。我们提出的研究将产生关于星形胶质细胞功能多样性的直接信息，并为未来的星形胶质细胞研究提供有用的工具，可以提供给整个神经科学界。

项目成果

G protein-coupled receptor 37-like 1 modulates astrocyte glutamate transporters and neuronal NMDA receptors and is neuroprotective in ischemia.

• DOI: 10.1002/glia.23198
• 发表时间: 2018-01
• 期刊: Glia
• 影响因子: 6.2
• 作者: Jolly S;Bazargani N;Quiroga AC;Pringle NP;Attwell D;Richardson WD;Li H
• 通讯作者: Li H

Rapid production of new oligodendrocytes is required in the earliest stages of motor-skill learning.

在运动技能学习的最早阶段需要快速产生新的少突胶质细胞

• DOI: 10.1038/nn.4351
• 发表时间: 2016-09
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Xiao, Lin;Ohayon, David;McKenzie, Ian A.;Sinclair-Wilson, Alexander;Wright, Jordan L.;Fudge, Alexander D.;Emery, Ben;Li, Huiliang;Richardson, William D.
• 通讯作者: Richardson, William D.

Motor skill learning requires active central myelination.

运动技能学习需要主动的中央髓鞘化。

• DOI: 10.1126/science.1254960
• 发表时间: 2014-10-17
• 期刊: Science (New York, N.Y.)
• 作者: McKenzie IA;Ohayon D;Li H;de Faria JP;Emery B;Tohyama K;Richardson WD
• 通讯作者: Richardson WD

New Olig1 null mice confirm a non-essential role for Olig1 in oligodendrocyte development.

• DOI: 10.1186/1471-2202-15-12
• 发表时间: 2014-01-14
• 期刊: BMC neuroscience
• 影响因子: 2.4
• 作者: Paes de Faria J;Kessaris N;Andrew P;Richardson WD;Li H
• 通讯作者: Li H

Evolution of the CNS myelin gene regulatory program.

• DOI: 10.1016/j.brainres.2015.10.013
• 发表时间: 2016-06-15
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Li H;Richardson WD
• 通讯作者: Richardson WD