Genetic and imaging studies of eye morphogenesis in development and disease

眼缺损包括一组常见的眼缺陷，影响所有年龄段的患者，但尤其是幼儿。这些病理是视力问题的常见原因，可导致视网膜脱离和白内障，并经常导致受影响患者失明。缺损通常是具有高度可变临床表现的遗传性疾病，通过检测眼睛的任何结构（包括角膜、视网膜、视神经或甚至眼睑）中的切口、间隙、孔或裂缝来诊断。与眼缺损相关的眼结构缺陷是由于眼胚胎形成失败所致。在胚胎发生期间，形成的眼睛和视神经经历戏剧性的形状变化，导致存在于眼睛一侧的裂隙（脉络膜裂隙）闭合，并最终形成眼睛地球仪。如果脉络膜裂的闭合被破坏，就会形成眼缺损。最近，一些先天性缺陷负责某些形式的缺损已被确定。这些缺陷包括错误或？突变？在某些基因中，这些基因通常使蛋白质在眼睛形成过程中发挥重要作用。尽管最近取得了这些进展，但我们对脉络膜裂闭合期间细胞的行为以及它们在缺损条件下如何受到影响几乎一无所知。了解这些问题是理解缺损病理学和找到治疗方法的基础。为此，我们将使用斑马鱼，一种小型条纹鱼，多年来一直被用作研究胚胎发育的模型，最近已成功用于模拟其他人类疾病。高度发达的成像技术允许在活体斑马鱼胚胎中观察发育中的眼睛。通过使用表现出与人类相似的缺损的斑马鱼，我们将比较这些缺损疾病模型和健康状况之间的脉络膜裂闭合过程。此外，我们还将进行一些遗传筛查，以寻找在缺损中受影响的其他基因。这些分析将为我们提供负责人类眼部病理的候选基因列表，将引导我们识别和生成人类眼部疾病的新模型，并使我们能够进一步了解正常的眼部发育和遗传性眼部畸形的原因。

Eye colobomas encompass a group of common eye defects affecting patients of all ages, but especially young children. These pathologies are a common cause of visual problems, can cause retinal detachment and cataracts, and often induce blindness in affected patients. Colobomas are generally hereditary diseases with a highly variable clinical presentation, being diagnosed by the detection of a notch, gap, hole or fissure in any of the structures of the eye, including the cornea, retina, optic nerve or even the eyelid. The defects in the ocular structures associated with the colobomas result from a failure in the embryonic formation of the eye. During embryogenesis, the forming eye and optic nerve undergo dramatic shape changes that lead to the closure of a fissure present on one side of the eye (the choroid fissure), and eventually to the formation of the eye globe. If choroid fissure closure is disrupted, an ocular coloboma develops. Recently, some of the congenital defects responsible for certain forms of coloboma have been identified. These defects consist of mistakes or ?mutations? in certain genes that normally make proteins important during eye formation. Despite these recent advances, we know virtually nothing about how cells behave during closure of the choroid fissure and how they are affected in coloboma conditions. Understanding these issues is fundamental to understand coloboma pathologies and to find ways of treating them. For this purpose, we will use the zebrafish, a small striped fish that has been used for years as a model to study embryonic development and that recently has been successfully used to model other human diseases. Highly developed imaging techniques allow visualisation of the developing eye in the living zebrafish embryo. By using zebrafish that exhibit colobomas similar to those in humans, we will compare the process of choroid fissure closure between these coloboma disease models and healthy conditions. In addition, we will perform a number of genetic screens to search for other genes affected in coloboma. These analyses will provide us with a list of candidate genes responsible for human ocular pathologies, will lead us to identify and generate new models for human eye diseases and will allow us to gain further insight into normal eye development and into the causes of hereditary ocular malformations.