Epigenetic regulation of neuronal regeneration after spinal cord lesion in zebrafish

斑马鱼脊髓损伤后神经元再生的表观遗传调控

• 批准号: 2115991
• 金额: --
• 依托单位: University of Edinburgh
• 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-2115991
• 关键词: Epigenetic; regulation; neuronal; regeneration; after

In contrast to mammals, zebrafish regenerate spinal neurons after injury (Becker and Becker, 2015).These new neurons replace lost ones and act as relays to bring about functional recovery. This is never observed in mammals. It is therefore important to determine how gene expressionprogrammes change in spinal progenitor cells after injury to allow for neurogenesis in zebrafish. In this PhD project in the Becker group (Edinburgh), the student will elucidate the epigeneticdeterminants of regenerative neurogenesis. The Becker group have established an efficient larval regeneration paradigm (Wehner et al., 2017) and preliminary observations indicate that epigenetichistone acetylation levels are altered after a lesion. Low acetylation levels are necessary for proper regeneration of motor neurons.AimsBased on these functional data the student will use bioinformatics approaches with the MacKenzie group (Aberdeen) to identify target sequences and downstream genes of these alterations ofacetylation (Hay et al., 2017). The importance of downstream genes will then be verified by in vivo perturbation experiments in zebrafish using CRISPR/Cas9 knock out and cell-type specific over- expression using the TetOn system. The student will work with a postdoc Dr Leonardo Cavone,funded by a new BBSRC project grant (to Thomas Becker, start date 15.10.2017).With this line of research, we hope to elucidate the intrinsic changes in spinal stem cells necessary for successful spinal cord regeneration. This project will provide targets for manipulations in endogenousmammalian stem cells, which invariably fail to generate neurons after injury.

与哺乳动物相比，斑马鱼在损伤后可以再生脊髓神经元（Becker and Becker, 2015）。这些新的神经元取代失去的神经元，并作为继电器带来功能恢复。这在哺乳动物中从未被观察到。因此，确定斑马鱼损伤后脊髓祖细胞中的基因表达程序如何改变以允许神经发生是很重要的。在这个博士项目在贝克组（爱丁堡），学生将阐明再生神经发生的表观遗传学决定因素。Becker小组已经建立了一种有效的幼虫再生模式（Wehner等人，2017），初步观察表明，表观遗传奇石酮乙酰化水平在病变后发生改变。低乙酰化水平是运动神经元正常再生所必需的。基于这些功能数据，学生将与MacKenzie团队（Aberdeen）一起使用生物信息学方法来识别这些面基化改变的靶序列和下游基因（Hay et al., 2017）。然后，下游基因的重要性将通过在斑马鱼中使用CRISPR/Cas9敲除和使用TetOn系统进行细胞类型特异性过表达的体内扰动实验来验证。该学生将与博士后Leonardo Cavone博士一起工作，由新的BBSRC项目资助（Thomas Becker，开始日期为2017年10月15日）。通过这一研究，我们希望阐明脊髓干细胞的内在变化是成功的脊髓再生所必需的。该项目将为内源性哺乳动物干细胞的操作提供靶点，这些干细胞在损伤后总是不能产生神经元。