Investigation of Heat shock Factor 1 as a Therapeutic Target for Huntington s Disease

热休克因子 1 作为亨廷顿病治疗靶点的研究

• 批准号: G0801314/1
• 负责人: Gillian Bates
• 金额: $ 194.16万
• 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: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0801314%2F1
• 关键词: Investigation; Heat; shock; Factor; Therapeutic

Increased life expectancy in the developed world has resulted in a greater incidence of age-related neurodegenerative disorders such as Alzheimer?s disease and Parkinson?s disease, which already impose a significant health, social and economic burden on families, communities and the country as a whole. Insight into the cause of these diseases has arisen through the study of rare genetic forms of Alzheimer?s and Parkinson?s disease as well as from inherited disorders like Huntington?s disease. The underlying mutations cause disease related proteins to misfold and adopt abnormal shapes allowing them to interact with themselves or other proteins in a detrimental manner. These aberrant interactions result in the malfunction and death of brain cells. Treatments that will slow or halt the progression of these ?protein-folding? diseases do not exist. All cells must ensure that as every protein is made, it is folded into the correct shape or conformation. Cells use ?chaperones? to fold proteins and if this is repeatedly unsuccessful, misfolded proteins are broken down or degraded. If this natural process to remove misfolded proteins becomes overwhelmed, as in the presence of a disease-related aggregation-prone protein, misfolded proteins accumulate and clump together as protein aggregates. The capacity of cells to maintain correctly folded proteins diminishes with age, resulting in an increasing susceptibility to protein-folding disease in the elderly. Strategies that might decrease the propensity of an aggregation-prone protein to misfold include increasing either the protein folding or protein degradation capacity of the cell. One possible approach is to harness the cells? natural defence against insults that cause proteins to misfold e.g. heat or toxic chemicals. This ?heat shock response? leads to the immediate increase in levels of many chaperones known as heat shock proteins and is switched on by heat shock factor 1 (HSF1). We have recently gained access to a drug that can cross the blood brain barrier and activate HSF1 in brain cells. We are also generating mouse models in which we can induce the presence of an activated form of HSF1 in brain. We shall use these complementary approaches understand the heat shock response in brain cells and to test whether activation of HSF1 can alleviate disease-related phenotypes in a mouse model of Huntington?s disease. This work will allow us to determine whether the activation of HSF1 should be pursued as a target for therapeutic development for Huntington?s disease and other neurodegenerative disorders.

发达国家预期寿命的增加导致了与年龄相关的神经退行性疾病（如阿尔茨海默病）的发病率增加。帕金森病与帕金森？艾滋病已经给家庭、社区和整个国家带来了沉重的健康、社会和经济负担。通过对阿尔茨海默病罕见遗传形式的研究，人们对这些疾病的病因有了更深入的了解。s和帕金森？以及遗传性疾病如亨廷顿舞蹈症？的疾病。潜在的突变导致疾病相关蛋白质错误折叠并采用异常形状，使它们能够以有害的方式与自身或其他蛋白质相互作用。这些异常的相互作用导致脑细胞的功能障碍和死亡。治疗将减缓或停止这些进展？蛋白质折叠疾病不存在。所有的细胞都必须确保每一个蛋白质都被折叠成正确的形状或构象。使用手机？监护人折叠蛋白质，如果这是反复失败，错误折叠的蛋白质被分解或降解。如果这种去除错误折叠蛋白质的自然过程变得不堪重负，就像在存在与疾病相关的易聚集蛋白质的情况下，错误折叠蛋白质就会积累并聚集在一起成为蛋白质聚集体。细胞维持正确折叠蛋白质的能力随着年龄的增长而降低，导致老年人对蛋白质折叠疾病的易感性增加。可能降低易聚集蛋白质错误折叠倾向的策略包括增加细胞的蛋白质折叠或蛋白质降解能力。一种可能的方法是利用细胞？对导致蛋白质错误折叠的损伤的天然防御，例如热或有毒化学物质。这个吗热休克反应？导致称为热休克蛋白的许多分子伴侣水平的立即增加，并由热休克因子1（HSF 1）开启。我们最近获得了一种药物，可以穿过血脑屏障并激活脑细胞中的HSF 1。我们也在制作小鼠模型，在这些模型中，我们可以诱导大脑中HSF 1的活化形式的存在。我们将使用这些互补的方法来了解脑细胞中的热休克反应，并测试是否激活HSF 1可以减轻亨廷顿病小鼠模型中的疾病相关表型？的疾病。这项工作将使我们能够确定是否激活HSF 1应追求作为一个目标的治疗发展亨廷顿？的疾病和其他神经退行性疾病。