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.

今天，世界上有5000多万人患有痴呆症，每年约有5500亿GB的资金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很小，迫切需要新药。设计有效的新药将需要更多地了解阿尔茨海默病的原因和如何发展，这一点目前在很大程度上仍然不清楚。我们确实知道，阿尔茨海默病的最初阶段涉及大脑中神经细胞的变化，特别是现在它们之间相互通信，这些变化似乎对推动疾病的发展非常重要。然而，这些变化是如何发生的在很大程度上是一个谜。明确的是，神经细胞内特定识别蛋白质行为方式的改变与人类疾病的出现密切相关。由于不可能直接在人类体内操控这些蛋白质，另一种方法是在动物体内操控表达。为了让我们相信这些研究有助于了解人类疾病的基础，动物模型准确地捕捉到人类疾病的特征是至关重要的。出于这个原因，这项工作的一个关键组成部分将是开发健壮的痴呆症和与智力残疾相关的小鼠模型，该模型紧密复制与人类认知障碍相关的神经病理学和疾病轨迹。有了这样的小鼠，就有可能进行非常具体的实验，试图确定导致这种疾病的变化。换句话说，在活着的老鼠身上，有可能检查疾病的进展，以及神经细胞和神经细胞之间的变化，以确定认知衰退的原因？然而，为了成功地实施这一办法，还需要有其他重要的实验要素。一种是一种健壮的方法，可以用来检测发生的任何变化。为此，必须开发能够测量这种变化的探测器。第二种是一种方法，可以在不干扰动物大脑的情况下测量探测器的输出。显然，大脑的破坏将危及这项研究，因为要确定是疾病还是大脑破坏导致认知能力下降将变得具有挑战性。出于这些原因，该项目将由一个来自日本和英国的科学家团队进行，他们在每个关键领域都有特定的专业知识：开发新的老鼠模型，开发新的探测器来检测动物神经系统的变化，以及开发创新的成像技术，利用这种技术在对神经系统几乎没有干扰的情况下对细胞进行成像。