New mouse models for tackling motor neuron disease and other neurodegenerative disorders.

用于治疗运动神经元疾病和其他神经退行性疾病的新小鼠模型。

• 批准号: G0801110/1
• 负责人: Elizabeth Fisher
• 金额: $ 121.49万
• 依托单位: University 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=G0801110%2F1
• 关键词: New; mouse; models; tackling; motor

This application is for a 4-year research project to create four new valuable mouse models in which to study neurodegeneration, with a long term view to finding therapeutics. These mouse strains complement and are different from existing models. During this award we will make the mice plus control strains, carry out initial ?clinical? analysis, and will make all the mice freely available to all other interested researchers. Motor neuron diseases (MNDs) are relatively common (in UK 1 in 400 death certificates is issued for some form of MND) and can strike at any age ? spinal muscular atrophy is the biggest single genetic killer of children world-wide, whereas amyotrophic lateral sclerosis (ALS) is a disease of mid-life that has a lifetime risk of up to 1 in 600. These diseases progress inexorably to paralysis and death and we have no treatments that improve quality of life or lifespan of sufferers. MNDs have a genetic component but for ALS only one major effect causative gene, SOD1 has been found (in 1993) and we still have no idea why the mutant form of the protein kills neurons. Recently a protein called TDP43 was identified which aggregates abnormally in the nerve cells of people suffering from ALS and in 2008 rare families have been identified who succumb to ALS with death in mid-life, because they have mutations in the TDP43 gene. TDP43 protein abnormalities have also been found in frontotemporal dementia (the most common form of dementia after Alzheimer?s disease), and Parkinson?s disease, Pick?s disease and other forms of neurodegeneration.Once a human mutant gene such as SOD1 or TDP43 has been identified, the next step is to genetically alter mice so that they recapitulate the human disease and we can study the pathological processes leading to illness and death. SOD1 transgenic mice have been tremendously helpful in understanding ALS, but have disadvantages. Currently no TDP43 mouse models exist. We want to create two new strains of mice, using newer technologies, which more closely model ALS in humans. These mice will be better for understanding human disease, for finding early ?biomarkers? of disease, and for trialling new therapies because they more closely replicate what is happening in humans. We will make the mice freely available to all researchers, without ties, by distributing them in the major mutant mouse repositories in Europe and USA for sending out to all research labs.

该申请适用于一个为期 4 年的研究项目，旨在创建四种新的有价值的小鼠模型来研究神经退行性疾病，并从长远角度寻找治疗方法。这些小鼠品系是对现有模型的补充，但又不同于现有模型。在这次颁奖期间，我们将让小鼠加上对照品系，进行初步的“临床”试验。分析，并将让所有其他感兴趣的研究人员免费使用所有小鼠。运动神经元疾病 (MND) 相对常见（在英国，每 400 份死亡证明中就有 1 份是因某种形式的 MND 签发的），并且可能发生在任何年龄？脊髓性肌萎缩症是全世界儿童最大的单一遗传杀手，而肌萎缩侧索硬化症 (ALS) 是一种中年疾病，其终生患病风险高达六百分之一。这些疾病会不可避免地发展为瘫痪和死亡，而我们没有任何治疗方法可以改善患者的生活质量或寿命。 MND 具有遗传成分，但对于 ALS，只有一个主要影响致病基因，SOD1 已被发现（1993 年），我们仍然不知道为什么该蛋白质的突变形式会杀死神经元。最近，一种名为 TDP43 的蛋白质被发现，它在 ALS 患者的神经细胞中异常聚集，2008 年，由于 TDP43 基因发生突变，一些罕见的家族被发现死于 ALS，并在中年死亡。在额颞叶痴呆（继阿尔茨海默病之后最常见的痴呆形式）、帕金森病、皮克氏病和其他形式的神经退行性疾病中也发现了 TDP43 蛋白异常。一旦识别出 SOD1 或 TDP43 等人类突变基因，下一步就是对小鼠进行基因改造，使它们重现人类疾病，我们就可以研究这种疾病。 导致疾病和死亡的病理过程。 SOD1 转基因小鼠对于理解 ALS 非常有帮助，但也有缺点。目前不存在 TDP43 小鼠模型。我们希望利用更新的技术培育出两种新的小鼠品系，以更接近地模拟人类 ALS。这些小鼠将更好地了解人类疾病，寻找早期“生物标志物”。疾病的研究，以及试验新疗法，因为它们更接近地复制了人类正在发生的情况。我们将把这些小鼠免费提供给所有研究人员，没有任何关系，将它们分发到欧洲和美国的主要突变小鼠存储库中，然后发送到所有研究实验室。