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

这项申请是一项为期4年的研究项目，旨在创建四种新的有价值的小鼠模型，以研究神经退行性疾病，并从长远角度寻找治疗方法。这些小鼠品系补充并不同于现有模型。在这个奖励期间我们将使小鼠加对照品系，进行初步的？临床？分析，并将使所有的小鼠免费提供给所有其他感兴趣的研究人员。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份是由于某种形式的MND），并且可以在任何年龄发作？脊髓性肌萎缩症是全世界儿童最大的单一遗传杀手，而肌萎缩性侧索硬化症（ALS）是一种中年疾病，其终生风险高达1/600。这些疾病无情地发展到瘫痪和死亡，我们没有改善患者生活质量或寿命的治疗方法。MND有一个遗传成分，但对于ALS只有一个主要的影响致病基因，SOD 1已被发现（1993年），我们仍然不知道为什么蛋白质的突变形式杀死神经元。最近发现了一种名为TDP 43的蛋白质，它在ALS患者的神经细胞中异常聚集，并且在2008年发现了一些罕见的家族，他们死于ALS并在中年死亡，因为他们在TDP 43基因中有突变。在额颞叶痴呆（阿尔茨海默病后最常见的痴呆形式？帕金森病（Parkinson？的疾病，皮克？一旦人类突变基因如SOD 1或TDP 43被鉴定出来，下一步就是对小鼠进行基因改造，使它们重现人类疾病，我们就可以研究导致疾病和死亡的病理过程。SOD 1转基因小鼠在理解ALS方面有很大的帮助，但也有缺点。目前不存在TDP 43小鼠模型。我们希望使用更新的技术创造两种新的小鼠品系，更接近人类ALS的模型。这些老鼠将更好地了解人类疾病，早期发现？生物标志物？以及试验新疗法，因为它们更接近于复制人类正在发生的事情。我们将把这些小鼠分发到欧洲和美国的主要突变小鼠仓库，然后发送到所有的研究实验室，让所有的研究人员都可以免费获得这些小鼠。

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.