Robustness in eye development: addressing the mechanisms behind eye formation and growth compensation

眼睛发育的稳健性：解决眼睛形成和生长补偿背后的机制

• 批准号: MR/X001067/1
• 负责人: Rodrigo Young
• 金额: $ 98.14万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX001067%2F1
• 关键词: Robustness; eye; development; addressing; mechanisms

The eye is made of diverse structures and cell types that enable light to be transformed into a nerve impulse that travels to the brain. Despite their complexity, eyes develop from the eye primordium, a single group of cells established during the third week of human gestation. These cells will bud apart laterally to form the two optic vesicles, which will keep growing independently and differentiate into the distinct cell types that make an eye.There are still many unanswered questions regarding eye formation, for example, why are some people born with smaller or no eyes? This project aims to answer this particular question by combining genetic analysis of patients that have developmental eye globe defects with research in zebrafish, this project aims to answer this particular question. Genes control embryo development, and when specific genes are impaired by mutations, people are born with morphological defects. Therefore, studying what goes wrong when genes are mutated provides information about their function. Knowing which genes are mutated in patients can help us understand how organs are formed and are also necessary for the development of therapies to prevent or cure disease. Currently, only 10% of patients born with anophthalmia (A, no eyes) or microphthalmia (M, very small eyes) can be genetically diagnosed with a single pathogenic mutation. For the rest, we do not know the responsible gene mutation, which limits both the possibility of appropriate medical care and of developing therapies.Humans and zebrafish eyes develop in a similar way, even using the same genes. Therefore, studying the genes that work in fish eye development is applicable to humans. In zebrafish, we can also mimic mutations found in patients and study their effects upon eye formation.I recently discovered that zebrafish mutants that develop an eye primordium with half the number of cells can continue growing until they reach the appropriate size due to a growth compensation mechanism. Hence, growth compensation can mask the effect of mutations, which could explain why it is difficult to find genes involved in eye defects. However, I also found that certain combinations of mutations can further impair eye formation leading to embryos with no eyes or with small underdeveloped eyes, like in human patients. The important question is: how can we identify more gene mutations that lead to eye formation defects?Building on my recent findings, and using tools I have generated, this project aims to: 1. Identify new gene mutations in patients with anophthalmia and microphthalmia.2. Validate mutations identified in anophthalmia and microphthalmia patients in zebrafish.3. Molecular and cell biological characterisation of validated genes and mutations.Overall, this project aims to identify new diagnostic genes for anophthalmic and microphthalmic patients, to enable appropriate genetic counselling, enhance our understanding of eye development, and set the grounds to generate new therapies.

眼睛是由各种结构和细胞类型制成的，可以使光转化为传播到大脑的神经冲动。尽管它们的复杂性，但眼睛是从眼睛原始的，这是在人类妊娠第三周建立的一组细胞。这些细胞将横向芽形成两个视线囊泡，它们会继续独立生长并区分出使眼睛的不同细胞类型。关于眼睛形成的不同问题，例如，为什么有些人出生于较小或没有眼睛？该项目旨在通过结合具有发育眼球缺陷的患者的遗传分析与斑马鱼研究的遗传分析来回答这个特定问题，该项目旨在回答这个特定的问题。基因控制胚胎发育，当特定基因受到突变损害时，人们天生就有形态缺陷。因此，研究基因突变时出了问题，提供了有关其功能的信息。知道哪些基因在患者中被突变可以帮助我们了解组织的形成方式，并且对于预防或治愈疾病的疗法也是必要的。目前，只有10％的患有疾病性的患者（A，无眼）或微观恐惧症（M，非常小的眼睛）可以被遗传诊断为单个致病性突变。对于其余的，我们不知道负责任的基因突变，这既限制了适当的医疗服务的可能性和开发疗法的可能性。人类和斑马鱼的眼睛以类似的方式发展，甚至使用相同的基因。因此，研究在鱼眼发育中起作用的基因适用于人类。在斑马鱼中，我们还可以模仿患者中发现的突变，并研究他们对眼睛形成的影响。我最近发现，斑马鱼突变体会发展出眼睛原始的斑马鱼突变体，其中一半的细胞数量可以继续生长，直到由于生长补偿机制而达到适当的大小。因此，生长补偿可以掩盖突变的效果，这可以解释为什么很难找到与眼缺陷有关的基因。但是，我还发现，某些突变的组合会进一步损害眼睛形成，导致没有眼睛或小欠发达的眼睛，就像人类患者一样。重要的问题是：我们如何确定更多导致眼睛形成缺陷的基因突变？在我最近的发现以及使用我生成的工具的基础上，该项目的目的是：1。识别疾病性疾病和微观恐惧症患者的新基因突变。2。在斑马鱼中验证的验证突变和微心氏症患者3。该项目旨在确定疾病和微观智能患者的新诊断基因，以实现适当的遗传咨询，增强我们对眼睛发育的理解，并为产生新的疗法树立新的疗法。