Modelling psychosis using DISC1 human induced pluripotent stem cells

使用 DISC1 人类诱导多能干细胞模拟精神病

• 批准号: MR/J004367/1
• 负责人: Andrew McIntosh
• 金额: $ 52.82万
• 依托单位: University of Edinburgh
• 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%2FJ004367%2F1
• 关键词: Modelling; psychosis; using; DISC1; human

Schizophrenia and major mental illness are very common conditions whose aetiology is imperfectly understood and for which our treatments are only partially effective. They are known to be highly familial (genetic) and some genetic risk factors, including those affecteing the DISC locus, are sufficient to cause these disorders in a large proportion of individuals who carry them. It is also known that abnormalities of brain structure and function are closely linked to these genetic factors. The cellular mechanisms underlying these abnormalities and clinical disorder are however still unclear, largely becuase the human brain is inaccessable in vivo. However, it has recently become possible to study brain cells in vitro by reprogramming skin fibroblasts to become neurones and other neural cell types. We propose to study in vitro neural tissue derived from individuals with and without disease-causing translocation at the DISC locus. First, we will reprogramme their fibroblasts to become pluripotent stem cells, neural progenitors and neurons which will then be extensively validated and characterised. We will then examine how disease risk is conferred at a cellular level through a series of comparative studies of neural progenitor proliferation, neuronal morphology and physiology, and later by focussing specifically on the processes affected DISC1/2 and glutamate (NMDA) receptor expression.

精神分裂症和重大精神疾病是非常常见的疾病，其病因尚不完全清楚，我们的治疗方法只有部分有效。众所周知，它们是高度家族性的(遗传)，一些遗传风险因素，包括那些影响椎间隙基因座的因素，足以在很大比例的携带者中导致这些疾病。众所周知，大脑结构和功能的异常与这些遗传因素密切相关。然而，这些异常和临床疾病背后的细胞机制仍然不清楚，很大程度上是因为在体内无法接触到人脑。然而，最近通过对皮肤成纤维细胞重新编程，使其成为神经元和其他类型的神经细胞，在体外研究脑细胞已经成为可能。我们建议在体外研究来自有或没有致病易位的个体的神经组织。首先，我们将对它们的成纤维细胞进行重新编程，使其成为多能干细胞、神经前体细胞和神经元，然后进行广泛的验证和鉴定。然后，我们将通过一系列关于神经前体细胞增殖、神经元形态和生理的比较研究，以及后来专门关注影响DISC1/2和谷氨酸(NMDA)受体表达的过程，来研究疾病风险是如何在细胞水平上被赋予的。

项目成果

Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness.

• DOI: 10.1038/s41398-021-01256-3
• 发表时间: 2021-02-19
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Bonneau M;Sullivan STO;Gonzalez-Lozano MA;Baxter P;Gautier P;Marchisella E;Hardingham NR;Chesters RA;Torrance H;Howard DM;Jansen MA;McMillan M;Singh Y;Didier M;Koopmans F;Semple CA;McIntosh AM;Volkmer H;Loos M;Fox K;Hardingham GE;Vernon AC;Porteous DJ;Smit AB;Price DJ;Kirsty Millar J
• 通讯作者: Kirsty Millar J

Improved PCR based methods for detecting C9orf72 hexanucleotide repeat expansions.

• DOI: 10.1016/j.mcp.2016.06.001
• 发表时间: 2016-08
• 期刊: Molecular and cellular probes
• 影响因子: 3.3
• 作者: Cleary EM;Pal S;Azam T;Moore DJ;Swingler R;Gorrie G;Stephenson L;Colville S;Chandran S;Porteous M;Warner JP
• 通讯作者: Warner JP

Maturation and electrophysiological properties of human pluripotent stem cell-derived oligodendrocytes.

• DOI: 10.1002/stem.2273
• 发表时间: 2016-04
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Livesey MR;Magnani D;Cleary EM;Vasistha NA;James OT;Selvaraj BT;Burr K;Story D;Shaw CE;Kind PC;Hardingham GE;Wyllie DJ;Chandran S
• 通讯作者: Chandran S

The cortical thickness phenotype of individuals with DISC1 translocation resembles schizophrenia.

• DOI: 10.1172/jci82636
• 发表时间: 2015-09
• 期刊: The Journal of clinical investigation
• 作者: Doyle OM;Bois C;Thomson P;Romaniuk L;Whitcher B;Williams SC;Turkheimer FE;Stefansson H;McIntosh AM;Mehta MA;Lawrie SM
• 通讯作者: Lawrie SM

Ionotropic GABA and glycine receptor subunit composition in human pluripotent stem cell-derived excitatory cortical neurones.

• DOI: 10.1113/jphysiol.2014.278994
• 发表时间: 2014-10-01
• 期刊: The Journal of physiology
• 作者: James OT;Livesey MR;Qiu J;Dando O;Bilican B;Haghi G;Rajan R;Burr K;Hardingham GE;Chandran S;Kind PC;Wyllie DJ
• 通讯作者: Wyllie DJ