Modelling inherited developmental ocular disorders using in vitro organoids

使用体外类器官模拟遗传性发育性眼部疾病

• 批准号: 2775365
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2775365
• 关键词: Modelling; inherited; developmental; ocular; disorders

Inherited developmental disorders account for much of childhood visual impairment, yet knowledge of their molecular and cellular causes is far from complete. During early eye development stem cells must balance fate decisions between proliferation and differentiation at the same time as undergoing cell migration and morphogenesis to prevent such disorders. Cell fate decisions are controlled by intrinsic factors, such as the gene network and extrinsic factors, such as mechanical signals from the surrounding tissue and extracellular matrix. Mechanical signals are crucial during eye development as mutations in the mechano-transducer YAP lead to coloboma in humans, a rare developmental disorder arising from failure in optic cup folding and fusion. Critically, the co-occurrence in many patients of coloboma, a structural disorder, and microphthalmia, a cell fate disorder, suggests a mechanistic link between the mechanical environment and cell fate in the developing eye. The hypothesis is that mutations that primarily lead to morphogenetic complications (i.e coloboma), then feedback to affect cell fate, resulting in co-occurrence of coloboma and microphthalmia. This project will involve introducing mutations from clinical reports into humanESCs and mouseES to set-up an in vitro model of coloboma/microphthalmia in retinal differentiation and optic cup organoid protocols. This will subsequently be used to explore the disease mechanisms and the control of cell fate decisions in the eye. These findings will advance understanding of the aetiology of developmental ocular disorders and will be more broadly applicable to the development and regeneration of other tissues. This project will also pave the way for using in-vitro organoids as a method for molecular diagnosis of developmental eye disorders.Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Zhong, X et al. (2014) Nature Communications.New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders. Holt R et al. (2017) Scientific Reports.

遗传性发育障碍是儿童视力障碍的主要原因，但对其分子和细胞原因的了解还远远不够。在早期眼睛发育过程中，干细胞必须在增殖和分化之间平衡命运的决定，同时进行细胞迁移和形态发生，以防止这种疾病。细胞命运的决定受内在因素如基因网络和外在因素如来自周围组织和细胞外基质的机械信号的控制。机械信号在眼睛发育过程中是至关重要的，因为机械传感器YAP的突变会导致人类结肠瘤，这是一种罕见的因光学杯折叠和融合失败而引起的发育障碍。重要的是，许多结肠瘤（一种结构紊乱）和小眼症（一种细胞命运紊乱）患者同时出现，表明发育中的眼睛的机械环境和细胞命运之间存在机制联系。假设突变主要导致形态发生并发症（即结肠瘤），然后反馈影响细胞命运，导致结肠瘤和小眼同时发生。该项目将涉及将临床报告中的突变引入人造血干细胞和小鼠内皮细胞，以建立视网膜分化和视杯类器官方案中的结肠瘤/小眼的体外模型。这将随后用于探索眼部疾病机制和细胞命运决定的控制。这些发现将促进对发育性眼部疾病病因的理解，并将更广泛地适用于其他组织的发育和再生。该项目还将为使用体外类器官作为发育性眼病分子诊断方法铺平道路。利用人多能干细胞生成具有功能光感受器的三维视网膜组织。钟旭等。（2014）《自然通讯》。新的变异和表达研究进一步揭示了与yap1相关的发育性眼病的基因型-表型相关性。Holt R et al.（2017）科学报告。