Resolving the basis of phenotypically variable hereditary abnormalities of eye formation

解决眼睛形成的表型变异遗传异常的基础

基本信息

批准号：
MR/T020164/1
负责人：
Stephen Wilson
金额：
$ 200.19万
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：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT020164%2F1
关键词：
Resolving basis phenotypically variable hereditary

项目摘要

Our eyes start out as outpocketings of brain tissue during early embryonic development. The cells destined to form the eyes originate within the neural plate, the precursor of the central nervous system. As the neural plate folds up to form the brain, the eye-forming cells bulge out laterally forming optic cups, the structures that later differentiate as eyes. Each optic cup undergoes shape changes and tissue fusion closes a gap (the optic fissure) present on one side of the cup, leading to formation of the intact globe shaped eye. The complex orchestration of cell movements that form the eyes is an example of morphogenesis - the process by which embryonic cells form into tissues and organs. Many of the genes that regulate the formation of the eye have yet to be identified. One reason that this lack of knowledge needs to be addressed is that congenital malformations of the eye, such as anophthalmia (lack of eyes), microphthalmia (small eyes) and coloboma (a failure in optic fissure fusion), being compatible with life and reproduction, are relatively common in the human population. As these are congenital defects, this means that eye problems are present from birth. While anophthalmic patients are blind, microphthalmic and coloboma patients can have severe visual impairment. For instance, colobomas are a common cause of visual problems, can cause retinal detachment and cataracts, and often lead to blindness.In this project, we will use zebrafish embryos to identify genes and genetic interactions important for eye formation. Zebrafish embryos are small, transparent and develop externally, facilitating the study of normal development and disease in the intact animal. Together with their amenability to genetic analysis, these features make fish embryos an excellent model system to study eye formation in normal and pathological conditions. Indeed, we can visualise all of the cells in the developing eye in living embryos both in healthy fish and in fish carrying one or more genetic mutations that compromise eye formation. Consequently, we can use research in fish both to identify those genes needed for eye formation and to understand the mechanisms by which such genes build functional eyes.Although some congenital abnormalities of eye formation are due to mutations in single genes, we suspect that in many cases, such defects are due to disruption of two or more genes. Consequently, in this project, we will use novel, powerful approaches that allow us to systematically analyse the consequences of simultaneous disrupted function of two or more genes that are candidates for causing eye defects when non-functional. To facilitate this research, our current MRC funding has enabled us to develop lines of fish carrying mutations that make the fish more likely to show eye phenoytpes when additional genes are disrupted. We will remove function of one or more additional genes in these "sensitised" fish lines to identify new genes and genetic interactions important for eye formation. We will also study the function of several genes that, when disrupted, give very similar eye defects both in fish and in humans as although we know these genes to be important, we do not understand how they function. Finally, we will study why individuals carrying the same genetic mutations can show quite different eye phenotypes. To facilitate this, we have lines of fish in which we can perform genetic or environmental perturbations that affect the severity of the eye defects. Overall, our research will help to bridge the gap between the highest quality research in model systems and human disease phenotypes. We will improve our understanding of normal eye development and will use new zebrafish models of human eye diseases to gain further insights into the causes of hereditary ocular malformations. Our research also has the potential to be of great value in the diagnosis of congenital abnormalities of eye formation.

我们的眼睛从早期胚胎发育期间的脑组织涌出开始。注定要形成眼睛的细胞起源于神经板，这是中枢神经系统的前体。随着神经板折叠成形成大脑，眼睛形成的细胞凸起侧面形成视杯，后来与眼睛区分的结构。每个光学杯都会发生形状变化，组织融合会缩小杯子一侧存在的间隙（视神经裂片），从而形成完整的球形眼。形成眼睛的细胞运动的复杂编排是形态发生的一个例子 - 胚胎细胞形成组织和器官的过程。许多调节眼睛形成的基因尚待鉴定。缺乏知识需要解决的原因之一是，眼睛的先天性畸形（例如，眼睛缺乏眼睛（缺乏眼睛），微观恐惧症（小眼睛）（小眼睛）和古罗巴马（视裂融合的失败），与生命和生命兼容，与生命和繁殖兼容，在人群中是相对常见的。由于这些是先天性缺陷，因此这意味着眼睛出生后会出现眼睛问题。虽然疾病患者是盲目的，但微脑症和成骨患者可能会受到严重的视力障碍。例如，糖瘤是视觉问题的常见原因，可能导致视网膜脱离和白内障，并且经常导致失明。在这个项目中，我们将使用斑马鱼胚胎来识别对眼睛形成重要的基因和遗传相互作用。斑马鱼的胚胎小，透明且在外部发展，促进了完整动物中正常发育和疾病的研究。这些特征将其对遗传分析的敏感性，使鱼类胚胎成为在正常和病理条件下研究眼睛形成的极好模型系统。确实，我们可以在健康鱼类和携带一种或多种损害眼睛形成的基因突变的鱼类和鱼类中的生存胚胎中形象化所有细胞。因此，我们可以在鱼类的研究中使用研究来鉴定眼睛形成所需的基因，并了解这种基因构建功能性眼睛的机制。尽管某些先天性眼睛形成的某些先天性异常是由于单个基因的突变引起的，我们怀疑在许多情况下，在许多情况下，这种缺陷是由于两个或多个基因的干扰。因此，在这个项目中，我们将使用新颖，有力的方法，使我们能够系统地分析两个或多个基因的同时中断功能的后果，这是候选者在非功能时引起眼缺陷的候选。为了促进这项研究，我们当前的MRC资金使我们能够开发出鱼类的携带突变线，从而使鱼类在破坏其他基因时更有可能表现出眼睛的恒星。我们将在这些“敏化”鱼类线中删除一个或多个其他基因的功能，以识别对眼睛形成很重要的新基因和遗传相互作用。我们还将研究几种基因的功能，当我们知道这些基因很重要，但我们不了解它们的功能，它们在鱼类和人类中都会产生非常相似的眼睛缺陷。最后，我们将研究为什么携带相同遗传突变的个体会显示出完全不同的眼睛表型。为了促进这一点，我们有一系列鱼类，可以在其中执行影响眼部缺陷严重程度的遗传或环境扰动。总体而言，我们的研究将有助于弥合模型系统中最高质量研究与人类疾病表型之间的差距。我们将提高对正常眼发育的理解，并将使用新的斑马鱼模型的人眼疾病模型，以进一步了解遗传性眼畸形的原因。我们的研究还有可能在诊断眼睛形成的先天性异常中具有巨大价值。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Foxd1-dependent induction of a temporal retinal character is required for visual function.

DOI：
10.1242/dev.200938
发表时间：
2022-12-15
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
通讯作者：

A versatile, automated and high-throughput drug screening platform for zebrafish embryos.

DOI：
10.1242/bio.058513
发表时间：
2021-09-15
期刊：
Biology open
影响因子：
2.4
作者：
Lubin A;Otterstrom J;Hoade Y;Bjedov I;Stead E;Whelan M;Gestri G;Paran Y;Payne E
通讯作者：
Payne E

Proteinase 3 promotes formation of multinucleated giant cells and granuloma-like structures in patients with granulomatosis with polyangiitis.

DOI：
10.1136/ard-2021-221800
发表时间：
2023-06
期刊：
Annals of the rheumatic diseases
影响因子：
27.4
作者：
通讯作者：

Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish.

DOI：
10.1242/dmm.044594
发表时间：
2022-06-01
期刊：
Disease models & mechanisms
影响因子：
4.3
作者：
通讯作者：

A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes.

DOI：
10.7554/elife.59683
发表时间：
2021-01-08
期刊：
eLife
影响因子：
7.7
作者：
Kroll F;Powell GT;Ghosh M;Gestri G;Antinucci P;Hearn TJ;Tunbak H;Lim S;Dennis HW;Fernandez JM;Whitmore D;Dreosti E;Wilson SW;Hoffman EJ;Rihel J
通讯作者：
Rihel J