Critical function of Kir4.1 for the life-long generation of oligodendrocytes and myelin

Kir4.1 对于少突胶质细胞和髓磷脂的终生生成的关键功能

• 批准号: MR/P025811/1
• 负责人: Arthur Butt
• 金额: $ 44.68万
• 依托单位: University of Portsmouth
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP025811%2F1
• 关键词: Critical; function; Kir4.1; life; long

The massive computing power of the brain depends on the insulation of nerve cell connections with myelin sheaths, by cells known as oligodendrocytes. Bundles of these 'myelinated' connections form the white matter that is very prominent in the human cortex. The loss of myelin is a feature of multiple neuropathologies, most notably Multiple Sclerosis and other demyelinating diseases. However, myelin loss is also important in the poor clinical outcomes of cerebral palsy, stroke, and traumatic injury. Importantly, oligodendrocytes are continuously being lost and regenerated from a pool of stem cells in the brain, called oligodendrocyte progenitor cells (OPCs). These regenerative processes are essential for the life-long maintenance of myelin and for repair of myelin following damage. The failure or impairment of repair results in the loss of myelin and can have devastating effects on brain function. We have identified a key factor that is essential for oligodendrocyte generation, known as Kir4.1 channels. The aim of this project is to determine the importance of Kir4.1 in OPCs in the life-long generation of oligodendrocytes and myelin and maintenance of a healthy brain. This will provide new knowledge on the mechanisms controlling the generation of myelin and how this may go wrong in pathology and may ultimately lead to the identification of new cellular targets for protecting the healthy brain.

大脑的巨大计算能力依赖于神经细胞与髓鞘的绝缘连接，这种绝缘连接是由被称为少突胶质细胞的细胞实现的。成束的这些“有髓鞘”的连接形成了白色物质，这在人类大脑皮层中非常突出。髓鞘的丢失是多种神经病理学的特征，最显著的是多发性硬化症和其他脱髓鞘疾病。然而，髓鞘丢失在脑瘫、中风和创伤性损伤的不良临床结果中也很重要。重要的是，少突胶质细胞不断丢失，并从大脑中的干细胞池中再生，称为少突胶质细胞祖细胞（OPC）。这些再生过程对于髓磷脂的终身维持和损伤后髓磷脂的修复至关重要。修复的失败或损伤导致髓鞘的损失，并可能对脑功能产生破坏性影响。我们已经确定了少突胶质细胞生成所必需的关键因素，称为Kir4.1通道。该项目的目的是确定OPCs中Kir4.1在少突胶质细胞和髓鞘的终身生成和健康大脑的维持中的重要性。这将提供关于控制髓鞘生成的机制的新知识，以及这在病理学中可能如何出错，并可能最终导致识别新的细胞靶点以保护健康的大脑。

项目成果

Resolving the age-related decline in central nervous system myelin turnover and drug discovery for oligodendroglial rejuvenation.

• DOI: 10.4103/1673-5374.338995
• 发表时间: 2022-12
• 期刊: NEURAL REGENERATION RESEARCH
• 影响因子: 6.1
• 作者: Rivera, Andrea Domenico;Butt, Arthur Morgan;Azim, Kasum
• 通讯作者: Azim, Kasum

Targeting the Subventricular Zone to Promote Myelin Repair in the Aging Brain.

靶向室内区域以促进衰老大脑的髓磷脂修复。

• DOI: 10.3390/cells11111809
• 发表时间: 2022-05-31
• 期刊: CELLS
• 影响因子: 6
• 作者: Butt, Arthur Morgan;Rivera, Andrea Dominico;Fulton, Daniel;Azim, Kasum
• 通讯作者: Azim, Kasum

Synaptic silencing affects the density and complexity of oligodendrocyte precursor cells in the adult mouse hippocampus

• DOI: 10.1101/2020.09.23.309682
• 发表时间: 2020-09
• 期刊: bioRxiv
• 作者: Irene Chacon-De-La-Rocha;Gemma L. Fryatt;Andrea D Rivera;L. Restani;M. Caleo;O. Raineteau;D. Gomez-Nicola;A. Butt

Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS.

• DOI: 10.1007/s00429-016-1199-8
• 发表时间: 2017-01
• 期刊: Brain structure & function
• 影响因子: 3.1
• 作者: Brasko C;Hawkins V;De La Rocha IC;Butt AM
• 通讯作者: Butt AM

Accelerated Dystrophy and Decay of Oligodendrocyte Precursor Cells in the APP/PS1 Model of Alzheimer's-Like Pathology.

阿尔茨海默氏病病理学的APP/PS1模型中的少突胶质细胞前体细胞的加速营养不良和衰减。

• DOI: 10.3389/fncel.2020.575082
• 发表时间: 2020
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Chacon-De-La-Rocha I;Fryatt G;Rivera AD;Verkhratsky A;Raineteau O;Gomez-Nicola D;Butt AM
• 通讯作者: Butt AM