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

肌萎缩侧索硬化症 (ALS) 中诱导多能干细胞 (iPS) 运动神经元的表征。

• 批准号: MR/K008943/1
• 负责人: Ke Ning
• 金额: $ 5.75万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK008943%2F1
• 关键词: Characterisation; motor; neurons; obtained; induced

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.

肌萎缩侧索硬化症（ALS）是一种破坏性的神经退行性疾病，影响上下运动神经元（MN），并导致诊断后2-3年内死亡。我们先前的发现和确定ALS患者MN转录谱以及研究其功能特征的可能性使我们与中国同济大学的Jun Xu教授等建立了合作。徐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。这项合作是一项共同努力，旨在有效地推进ALS研究，融合技术专长和大量生物样本。应用微阵列技术分析患者和对照的诱导多能干细胞（iPS）来源的运动神经元（MN），将揭示肌萎缩侧索硬化症（ALS）中失调的基因和通路。这项研究计划将阐明MN的选择性脆弱性，从而确定潜在的治疗靶点。本研究的目的是：1.由我们在中国同济大学的合作者生产iPS衍生的MN，并在英国谢菲尔德的主机实验室建立该技术。2.确定iPS衍生的MN 3的表达谱。比较散发性和家族性ALS患者与对照组MN的表达谱。4.为了确定与对照相比从患者获得的MN的应激反应，以及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衍生的ALS细胞在培养基中释放的细胞因子和其他因子及其对对照MN的影响。6.比较患者源性MN和对照源性MN的轴突运输特征。7.检测能够拮抗或诱导通过上述研究确定的相关途径的药物。

项目成果

SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits.

• DOI: 10.1038/ncomms16063
• 发表时间: 2017-07-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Hautbergue GM;Castelli LM;Ferraiuolo L;Sanchez-Martinez A;Cooper-Knock J;Higginbottom A;Lin YH;Bauer CS;Dodd JE;Myszczynska MA;Alam SM;Garneret P;Chandran JS;Karyka E;Stopford MJ;Smith EF;Kirby J;Meyer K;Kaspar BK;Isaacs AM;El-Khamisy SF;De Vos KJ;Ning K;Azzouz M;Whitworth AJ;Shaw PJ
• 通讯作者: Shaw PJ

Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease.

• DOI: 10.1111/acel.13281
• 发表时间: 2021-01
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Gatto N;Dos Santos Souza C;Shaw AC;Bell SM;Myszczynska MA;Powers S;Meyer K;Castelli LM;Karyka E;Mortiboys H;Azzouz M;Hautbergue GM;Márkus NM;Shaw PJ;Ferraiuolo L
• 通讯作者: Ferraiuolo L

Quantitative proteomic analysis of age-related subventricular zone proteins associated with neurodegenerative disease.

与神经退行性疾病相关的年龄相关室下区蛋白的定量蛋白质组学分析。

• DOI: 10.1038/srep37443
• 发表时间: 2016-11-18
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Wang X;Dong C;Sun L;Zhu L;Sun C;Ma R;Ning K;Lu B;Zhang J;Xu J
• 通讯作者: Xu J

Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis.

• DOI: 10.1016/j.neuron.2021.12.019
• 发表时间: 2022-03-16
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Zhang S;Cooper-Knock J;Weimer AK;Shi M;Moll T;Marshall JNG;Harvey C;Nezhad HG;Franklin J;Souza CDS;Ning K;Wang C;Li J;Dilliott AA;Farhan S;Elhaik E;Pasniceanu I;Livesey MR;Eitan C;Hornstein E;Kenna KP;Project MinE ALS Sequencing Consortium;Veldink JH;Ferraiuolo L;Shaw PJ;Snyder MP
• 通讯作者: Snyder MP

Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis.

• DOI: 10.1186/s13024-017-0227-3
• 发表时间: 2017-11-13
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Ciervo Y;Ning K;Jun X;Shaw PJ;Mead RJ
• 通讯作者: Mead RJ