Genetic and imaging studies of eye morphogenesis in development and disease

眼结肠瘤包括一组常见的眼睛缺陷，影响所有年龄的患者，但尤其是幼儿。这些病变是视力问题的常见原因，可引起视网膜脱离和白内障，并经常导致患者失明。结肠瘤通常是一种具有高度可变临床表现的遗传性疾病，通过检测眼睛任何结构（包括角膜、视网膜、视神经甚至眼睑）中的缺口、间隙、孔或裂隙来诊断。与结肠瘤相关的眼部结构缺陷是由于眼睛胚胎形成失败造成的。在胚胎发育过程中，形成的眼睛和视神经经历了剧烈的形状变化，导致眼睛一侧的裂缝（脉络膜裂缝）闭合，并最终形成眼球。如果脉络膜裂隙闭合被破坏，就会形成眼结肠瘤。最近，一些先天性缺陷负责某些形式的结肠瘤已被确定。这些缺陷由错误或突变组成。在眼睛形成过程中产生重要蛋白质的某些基因中。尽管最近取得了这些进展，但我们实际上对细胞在脉络膜裂隙闭合过程中的行为以及它们在结肠畸形条件下如何受到影响一无所知。了解这些问题是了解结肠瘤病理并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，最近已成功地用于模拟其他人类疾病。高度发达的成像技术可以使活斑马鱼胚胎中发育中的眼睛可视化。通过使用表现出与人类相似的结肠瘤的斑马鱼，我们将比较这些结肠瘤疾病模型和健康状况之间脉络膜裂隙闭合的过程。此外，我们将执行一些基因筛选，以寻找其他基因影响结肠瘤。这些分析将为我们提供一份负责人类眼部病理的候选基因清单，将引导我们识别和生成人类眼部疾病的新模型，并将使我们进一步了解正常眼睛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.