Establishing clinically relevant zebrafish animal models to study abnormal retinal development using CRISPR-Cas9 mutagenesis

CRISPR-Cas9诱变技术的发展彻底改变了我们研究人类疾病的能力，并创造了具有明确转化潜力的动物模型。在这个项目中，学生将使用最现代的诱变技术来创建影响视觉系统的基因突变的“人性化”斑马鱼模型。我们将对本地下一代测序研究和100,000基因组项目中的基因突变进行建模，以快速表征斑马鱼模型中的功能影响。这将有助于从良性变异中确定致病变异的优先级，并确定对参与视觉系统发育的已知和候选基因的影响。斑马鱼的结构和功能特征将通过高分辨率成像技术和最先进的视觉行为和电生理分析来实现。斑马鱼是一种理想的模式生物，因为它易于遗传操作，胚胎透明，发育迅速，具有与人类相似的强大视觉反应。建立斑马鱼突变系将为随后进行药理学分析以试验潜在治疗提供机会。

The development of CRISPR-Cas9 mutagenesis has revolutionised our ability to study human diseases and create animal models with clear translational potential. In this project, the student will use the most modern mutagenesis techniques to create "humanised" zebrafish models of genetic mutations that affect the visual system. We will model genetic mutations from both our local next generation sequencing studies and the 100,000 genomes project to rapidly characterise the functional impact within a zebrafish model. This will help prioritise pathogenic variants from benign variants and identify impact on known and candidate genes involved in development of the visual system. Structural and functional characterisation of the zebrafish will be achieved using high resolution imaging techniques and state-of-the art visual behavioural and electrophysiological assays. The zebrafish is an ideal model organism due to its ease of genetic manipulation, transparency of embryos and rapid development with robust visual responses similar to humans. Establishment of zebrafish mutant lines will provide the opportunity to subsequently carry out pharmacological assays to trial potential treatments.