Implementing an MEA platform in human neurones for studying age-related neural network dysfunction and testing dietary interventions

在人类神经元中实施 MEA 平台，用于研究与年龄相关的神经网络功能障碍并测试饮食干预

• 批准号: NC/X00189X/1
• 负责人: Robert Williams
• 金额: $ 22.5万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FX00189X%2F1
• 关键词: Implementing; MEA; platform; human; neurones

Cognitive decline and other symptoms of brain ageing are caused by a loss of connections between cells resulting in communication failure known as neuronal network dysfunction. Adaptation of the human diet to deliver specific well-tolerated protective components, either in food, as nutraceutical supplements or as mimics of conventional medicines, is a potentially attractive cost-effective strategy for preserving these connections thus promoting healthy brain ageing, particularly during the long phases of dementia. Our research goal is to identify the most effective dietary molecules and to achieve this aim, we are investigating the molecular mechanisms underpinning age-related cognitive decline and in parallel we are testing natural products with a focus on dietary polyphenols. Like many other research laboratories we have been undertaking almost all our work in mouse models and in mouse cells but it is now viewed as critical to the field that future studies are tested under more relevant conditions in human cells. This is partly because of ethical concerns regarding the use of rodents but is also due to clear species specific differences in the way that mice and humans respond to dietary interventions. It is therefore, only through adopting new approaches in human cells that we can have any real confidence that information gained can be translated into improvements in human health. Moving our research into human cells is a significant challenge for us because growing human brain cells, specifically neurones, in the laboratory is not at all straightforward and whether these cells can be used to model age-related neuronal network dysfunction has not been established. We therefore propose to make a step change in our approach by growing neurones from human embryonic stem cells rather than from mice, and combining this with state-of-the-art microelectrode array technology to record the neuronal network that forms between these cells. We will mimic age-related changes by introducing toxic proteins that are known to accumulate in the ageing brain. If successful this will deliver an advanced human cell system for studying the molecular mechanisms of brain ageing, a more physiologically relevant model for testing dietary polyphenols and ultimately we anticipate will lead to the significant replacement of mouse models for this research area.

认知能力下降和大脑衰老的其他症状是由于细胞之间失去连接导致通信失效的神经元网络功能障碍而引起的。适应人类饮食以提供特定耐受性良好的防护成分，无论是食物中的营养补充剂还是传统药物的模仿，是一种潜在的具有吸引力的成本效益的策略，可保留这些连接，从而促进健康的大脑衰老，尤其是在痴呆症的长期期间。我们的研究目标是确定最有效的饮食分子并实现这一目标，我们正在研究与年龄相关认知能力下降的分子机制，并且同时我们正在测试以饮食多酚的重点测试天然产品。像许多其他研究实验室一样，我们几乎在小鼠模型和小鼠细胞中都从事所有工作，但是现在被认为对现场的研究至关重要，即未来的研究在人类细胞中更相关的条件下进行了测试。这部分是由于对啮齿动物使用的道德问题，但也是由于小鼠和人类对饮食干预措施做出反应的方式的明显特定差异所致。因此，只有通过在人类细胞中采用新方法，我们才能真正相信获得的信息才能转化为人类健康的改善。对我们来说，将我们的研究转移到人类细胞上是一个重大挑战，因为在实验室中，人类脑细胞（特别是神经元）并非完全直接，并且这些细胞是否可用于模拟与年龄相关的神经元网络功能障碍进行建模。因此，我们建议通过从人类胚胎干细胞而不是从小鼠中种植神经元来改变我们的方法，并将其与最新的微电极阵列技术结合起来，以记录这些细胞之间形成的神经元网络。我们将通过引入已知会在衰老大脑中积聚的有毒蛋白来模仿与年龄相关的变化。如果成功的话，这将提供一个先进的人类细胞系统，用于研究脑衰老的分子机制，这是一个更相关的测试饮食多酚的模型，最终我们预计将导致该研究领域的小鼠模型的显着替代。