Characterisation of the motor neurons obtained from induced pluripotent stem cells (iPS) in Amyotrophic lateral sclerosis (ALS).

肌萎缩性侧索硬化症（ALS）是一种影响上下运动神经元（MN）的破坏性神经退行性疾病，可在诊断后2-3年内导致死亡。我们之前的研究结果以及确定ALS患者MN转录谱的可能性以及调查其功能特征使我们与中国同济大学徐军教授等人建立了合作关系。许军教授和高正良教授在同济大学干细胞研究中心建立了非常好的干细胞研究设施。他们在干细胞研究方面拥有国际公认的记录，并成功地从人类成纤维细胞中产生了运动神经元样细胞。此次合作是双方的共同努力，旨在有效推进ALS研究，融合技术专长和大量生物样本。应用微阵列分析来自患者和对照组的诱导多能干细胞（iPS）衍生的运动神经元（MN）将揭示肌萎缩性侧索硬化症（ALS）中失调的基因和通路。该研究计划将阐明MN的选择性易感性，从而确定潜在的治疗靶点。本研究的目的是：1。从我们在中国同济大学的合作者那里生产ips衍生的MN，并在英国谢菲尔德的宿主实验室建立该技术。2. 目的：确定ips衍生的mn3的表达谱。比较散发性和家族性ALS患者的MN表达谱与对照组的差异。4. 为了确定从患者和对照组中获得的MN的应激反应，并比较来自同一个体的MN和成纤维细胞的应激反应5。鉴定ips来源的ALS细胞在培养基中释放的细胞因子及其对对照MN的影响。6. 比较患者源性MN与对照组源性MN的轴突转运特性。7. 测试能够拮抗或诱导通过上述调查确定的相关途径的药物。

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder affecting upper and lower motoneurons (MN) and leading to death within 2-3 years from diagnosis. Our previous findings and the possibility to determine the transcription profile of MN derived from ALS patients as well as investigating their functional characteristics led us to set up a collaboration with Professor Jun Xu et al at Tongji University in China. Professor Jun Xu and Professor Zhengliang Gao have established very good stem cell research facility at Stem Cell Research Center at Tongji University. They have international recognised track records in stem cell research and have successfully produced motor neuron like cells from human fibroblast cells. This collaboration is a joint effort to efficiently progress in ALS research, merging technical expertise and a large number of biological samples. The application of microarray analysis to the induced pluripotent stem cells (iPS) derived motor neurones (MN) from patients and controls will uncover the genes and pathways dysregulated in Amyotrophic lateral sclerosis (ALS). This research programme will elucidate the selective vulnerability of MN allowing the identification of potential therapeutic targets. The aims of the proposed study are: 1. To produce iPS-derived MN from our collaborators at Tongji University in China and set up the technique in the host laboratory in Sheffield, UK. 2. To determine the expression profile of the iPS-derived MN 3. To compare the expression profile of MN derived from sporadic and familial ALS patients with control. 4. To determine the stress response of MN obtained from patients compared to controls as well as comparing the stress response of MN and fibroblasts from the same individual 5. To identify the cytokines and other factors released in the media by the iPS-derived ALS cells and their effect on control MN. 6. To compare the axonal transport characteristics of patient derived MN with control derived MN. 7. To test drugs able to antagonise or induce relevant pathways identified through the investigations outlined above.