An interrogation of synaptic dysfunctions arising from human cognitive disease gene mutations using opto-physiological and neurochemical strategies.

使用光生理学和神经化学策略对人类认知疾病基因突变引起的突触功能障碍进行研究。

• 批准号: MR/X02170X/1
• 负责人: N Emptage
• 金额: $ 60.74万
• 依托单位: University of Oxford
• 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=MR%2FX02170X%2F1
• 关键词: interrogation; synaptic; dysfunctions; arising; human

More than 50 million people in the world are living with dementia today, and approximately £550 billion is spent each year on their health and social care. Alzheimer's disease is the most common type of dementia, but current treatments have very little effect on the disease, and the need for new medicines is urgent. Designing effective new medicines will require a greater understanding of why and how Alzheimer's disease develops, something that currently remains largely obscure. We do know that the very first stages of Alzheimer's disease involve changes to nerve cells in the brain, and in particular now they communicate with each other, and that these changes seem to be important in driving forward the progression of the disease. However, how the changes come about is largely a mystery. What is clear is that alterations in the way specific identified proteins behave within nerve cells are closely associated with the appearance of the disease in humans. As it is not possible to manipulate these proteins directly in humans an alternative approach is to manipulate the expression in animals. For us to be confident that such studies are informative in helping understand the basis of human disease it is essential that the animal models accurately capture the features of the human disease. For this reason a key component of the work will be the development of robust dementia and intellectual disability-related mouse models that closely replicate the neuropathology and disease trajectories associated with dysfunctional cognition in humans. With such mice it is then possible to perform quite specific experiments that seek to identify the changes that are driving the disease. Said another way, in living mice it is possible to examine the progression of the disease, along with the changes at and between nerve cells, in order to identify the cause of the cognitive decline? There are however other important experimental elements that need to be in place in order that this approach can be successful implemented. One is a robust method with which to detect any changes that have occurred. For this probes must be developed that are able to measure such changes. The second is a method where the output from the probes can be measured without disrupting the brain of the animal. Clearly disruption of the brain would compromise the study as it would become challenging to determine whether the disease or the disruption was responsible for the cognitive decline. For these reasons the project will to be conducted by a team of scientists from Japan and the UK who have specific expertise in each of the key areas: the development of new mouse models, the development of new probes for the detection of changes within the animal's nervous system and the development of innovative imaging technologies with which to image cells with little or no disruption to the nervous system.

如今，世界上有超过 5000 万人患有痴呆症，每年大约花费 5500 亿英镑用于他们的健康和社会护理。阿尔茨海默病是最常见的痴呆症类型，但目前的治疗方法对该疾病的效果甚微。设计有效的新药物迫在眉睫，需要更好地了解阿尔茨海默病的发病原因和方式，而目前我们确实知道阿尔茨海默病的第一阶段涉及神经细胞的变化。在大脑，特别是现在它们相互交流，这些变化似乎对推动疾病的进展很重要，但是，这些变化是如何发生的在很大程度上是一个谜。神经细胞内特定的蛋白质行为与人类疾病的出现密切相关，因为不可能直接在人类中操纵这些蛋白质，另一种方法是操纵动物中的表达，让我们对此类研究充满信心。动物模型对于帮助理解人类疾病的基础提供了丰富的信息，这一点至关重要因此，这项工作的一个关键组成部分是开发强大的痴呆症和智力障碍相关小鼠模型，该模型可以精确地复制与人类认知功能障碍相关的神经病理学和疾病轨迹。然后可以进行非常具体的实验，试图找出导致疾病的变化。换句话说，在活体小鼠中，可以检查疾病的进展，以及神经细胞之间和神经细胞之间的变化。为了找出认知能力下降的原因？然而，为了成功实施这种方法，还需要具备其他重要的实验要素，其中之一是检测已发生的任何变化的稳健方法，必须开发能够测量此类变化的探针。第二种方法可以在不破坏动物大脑的情况下测量探针的输出，显然，大脑的破坏会损害研究，因为确定疾病或破坏是否是造成这种变化的原因变得困难。由于这些原因，该项目将由一个团队进行。来自日本和英国的科学家在每个关键领域都拥有特定的专业知识：新小鼠模型的开发、用于检测动物神经系统变化的新探针的开发以及创新成像技术的开发对神经系统很少或没有干扰的细胞成像。