Molecular mechanisms underlying replicative stress and genome damage in pluripotent stem cells

多能干细胞复制应激和基因组损伤的分子机制

• 批准号: 2283666
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2283666
• 关键词: Molecular; mechanisms; underlying; replicative; stress

Pluripotent stem cells (PSCs) in the early embryo give rise to all ofthe somatic cells in the body. Maintenance of the genetic integrity of PSCs isessential for preventing genetic defects to be passed onto multiple progeny cells,which would be detrimental for a developing embryo. When placed underappropriate culture conditions, PSCs retain the ability to give rise to differentiatedcells from all three embryonic germ layers, whilst acquiring the ability to self-renew extensively and thus provide an excellent, genetically normal modelsystem to investigate mechanisms that control genome integrity. We and othershave previously shown that PSCs acquire non-random genetic changes uponprolonged culture. However, the molecular mechanisms underlying theiracquisition remain poorly understood. To this end, our project will determine thecontribution of different genome damage mechanisms to the common geneticchanges we observe. We will also elucidate how extrinsic environment(specifically, culture medium composition) enhance or diminish these damagemechanisms. Our previous data has shown that growing cells in different culturemedia and environmental conditions significantly alters their mutation rates.Work from other groups highlighted albumin as a key component of the medium,necessary for stabilizing small molecules and ions and scavenging free radicalsthat could be harmful for macromolecules, particularly the DNA. Hence, incollaboration with our industrial partner Albumedix, who specializes inrecombinant albumin production, we will determine the contribution of intrinsicmechanisms and niche conditions on genome damage of PSCs.

早期胚胎中的多能干细胞（PSCs）产生体内所有的体细胞。维持PSC的遗传完整性对于防止遗传缺陷传递到多个后代细胞是至关重要的，这对发育中的胚胎是有害的。当置于适当的培养条件下时，PSC保留了从所有三个胚胎胚层产生分化细胞的能力，同时获得广泛的自我更新能力，从而提供了一个极好的、遗传上正常的模型系统来研究控制基因组完整性的机制。我们和其他人先前已经表明PSC在长期培养中获得非随机的遗传变化。然而，其获得的分子机制仍然知之甚少。为此，我们的项目将确定不同的基因组损伤机制与我们观察到的常见遗传变化的关系。我们还将阐明外部环境（特别是培养基成分）如何增强或减弱这些损伤机制。我们以前的数据表明，在不同的培养基和环境条件下生长的细胞会显著改变它们的突变率。其他小组的工作强调白蛋白是培养基的关键成分，它对稳定小分子和离子以及清除可能对大分子有害的自由基（尤其是DNA）是必要的。因此，在与我们的工业合作伙伴Albumedix（专门从事重组白蛋白生产）的合作下，我们将确定内在机制和生态位条件对PSC基因组损伤的贡献。