Evaluation of the kinases responsible for tau toxicity

评估负责 tau 毒性的激酶

• 批准号: G0500261/1
• 负责人: Guy Justin Clive Tear
• 金额: $ 37.61万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0500261%2F1
• 关键词: Evaluation; kinases; responsible; tau; toxicity

Neurodegenerative diseases such as Alzheimer?s disease are extremely debilitating and distressing. As Alzheimer?s disease mainly affects older people and the current demographic trend is towards a population that continues to live longer the impact of Alzheimer?s will increase significantly. To allow more effective treatments to be developed more needs to be understood about the underlying causes of the disease. It is currently recognised that there is an abnormal build-up of protein in the brain cells of Alzheimer?s sufferers which results in the loss of nerve cells which leads ultimately to dementia. Much work has previously established that a protein known as tau is one of the proteins that accumulates in diseased cells. Tau normally has an important role for nerve cell function but in Alzheimer?s disease this protein begins to function abnormally. In the disease state the tau protein that builds up is chemically altered by the abnormal addition of excess amounts of phosphate. One hope for the development of treatments for Alzheimer?s disease is to find drugs that block the enzymes (known as kinases) that add this phosphate onto the tau protein. Several candidate kinases have been identified and we now need to identify which of the kinases is a major contributor to the formation of toxic tau protein in diseased cells. It is not possible to do this in human and is also difficult to do rapidly in mouse. In this project we will use the fruit fly (Drosophila) as a model system where we can accurately and efficiently evaluate which of the kinases are responsible for the production of abnormally phosphorylated tau. By identifying the kinases that are responsible we will enable the development of more effective therapies. We also plan to investigate whether we can use Drosophila as an assay system to test the effectiveness of drugs that may alleviate the causes of Alzheimer?s disease. As the work that we plan to do may have significant implications for the future treatment of a well known disease we will endeavour to make the results of our work available to the general public by presenting significant advances on our website, through peer-reviewed publications and where appropriate through press announcements.

阿尔茨海默病等神经退行性疾病会使人极度虚弱和痛苦。由于阿尔茨海默病主要影响老年人，并且当前的人口趋势是人口寿命持续延长，因此阿尔茨海默病的影响将显着增加。为了开发出更有效的治疗方法，需要更多地了解该疾病的根本原因。目前人们认识到，阿尔茨海默病患者的脑细胞中蛋白质异常积聚，导致神经细胞损失，最终导致痴呆。此前的许多工作已经证实，一种名为 tau 的蛋白质是在患病细胞中积累的蛋白质之一。 Tau 通常对神经细胞功能发挥重要作用，但在阿尔茨海默病中，这种蛋白质开始功能异常。在疾病状态下，过量磷酸盐的异常添加会导致积累的 tau 蛋白发生化学变化。开发阿尔茨海默病治疗方法的一个希望是找到能够阻断将这种磷酸盐添加到 tau 蛋白上的酶（称为激酶）的药物。几种候选激酶已经被鉴定出来，我们现在需要确定哪种激酶是患病细胞中有毒 tau 蛋白形成的主要贡献者。在人类中不可能做到这一点，在小鼠中也很难快速做到这一点。在这个项目中，我们将使用果蝇（果蝇）作为模型系统，我们可以准确有效地评估哪些激酶负责异常磷酸化 tau 的产生。通过识别负责的激酶，我们将能够开发出更有效的疗法。我们还计划研究是否可以使用果蝇作为检测系统来测试可能减轻阿尔茨海默病病因的药物的有效性。由于我们计划开展的工作可能对一种众所周知的疾病的未来治疗产生重大影响，因此我们将努力通过在我们的网站上展示重大进展、通过同行评审的出版物以及在适当的情况下通过新闻公告，向公众提供我们的工作结果。