Investigation of genetic variation in MSH3, a DNA repair protein that modifies the course of Huntington's disease

MSH3（一种改变亨廷顿病病程的 DNA 修复蛋白）遗传变异的研究

• 批准号: 2074106
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2074106
• 关键词: Investigation; genetic; variation; MSH3; DNA

Huntington's disease (HD) is a fatal neurodegenerative condition caused by a CAG repeat mutation in the huntingtin gene (Htt). A recent Genome Wide Association Study (GWAS) performed in HD patients identified MSH3, a mismatch repair gene, as a key genetic modifier associated with the rate of disease progression[1]. This signal is driven by a three-repeat allele in MSH3 exon 1, associated with a reduced rate of somatic expansion, delayed disease onset and slower disease progression [2].This PhD project is aimed at understanding the mechanisms by which the three-repeat allele results in slower disease progression in HD. Its effects on the normal DNA repair function of MSH3, its interaction with binding partners in the MMR pathway, and the effects on somatic expansion will be examined in multiple cell systems - including U20S cells, as well as patient-derived lymphoblastoids and iPSC's, which can be differentiated into medium spiny neurons, the cell-type most significantly affected in HD. The therapeutic potential of MSH3 modulation will also be explored using MSH3 ASOs (Anti-Sense Oligonucleotides) and small molecules affecting binding interactions. If time permits, the relevance to other trinucleotide repeat diseases will also be explored.

亨廷顿病（HD）是由亨廷顿基因（Htt）中的CAG重复突变引起的致命性神经退行性疾病。最近在HD患者中进行的全基因组关联研究（GWAS）确定MSH 3（一种错配修复基因）是与疾病进展速率相关的关键遗传修饰因子[1]。该信号由MSH 3外显子1中的三重复等位基因驱动，与体细胞扩张速率降低、疾病发作延迟和疾病进展缓慢相关[2]。本博士项目旨在了解三重复等位基因导致HD疾病进展缓慢的机制。它对MSH 3的正常DNA修复功能的影响，它与MMR途径中的结合伴侣的相互作用，以及对体细胞扩增的影响将在多个细胞系统中进行检查-包括U20 S细胞，以及患者来源的淋巴母细胞和iPSC，其可以分化为中等多刺神经元，HD中受影响最显著的细胞类型。还将使用MSH 3 ASO（反义寡核苷酸）和影响结合相互作用的小分子探索MSH 3调节的治疗潜力。如果时间允许，还将探索与其他三核苷酸重复疾病的相关性。