调控眼胚裂融合的细胞和分子机理的研究

眼胚裂（optic fissure）是视网膜形态发生过程中形成的临时性裂隙，后将完全融合。眼胚裂融合失败将在视网膜腹侧留下永久性裂隙，被称为视网膜缺损（coloboma）。视网膜缺损是导致儿童视力障碍，甚至失明的严重先天性遗传眼病。当前，对眼胚裂融合的细胞和分子机理的研究尚肤浅，这使得研究视网膜缺损的病因学变得困难。我们的前期工作提示眼胚裂融合是时空上精确调控的形态发生过程，涉及到融合部位广泛的细胞-细胞和细胞-细胞外基质的重组。然而，我们对执行眼胚裂融合组织重组程序的基质蛋白酶和细胞骨架调控蛋白，以及调控它们时空精确表达和功能的机制一无所知。在本项目中，我们将从分析眼胚裂两侧视杯组织中高度特异性表达的基因入手，结合转录基因组学，细胞生物学，分子生物学，小鼠和斑马鱼遗传学等手段，寻找执行眼胚裂融合的功能基因，深入探讨调控眼胚裂融合的细胞和分子机理，为视网膜缺损的诊断和治疗提供理论基础

Optic fissure is a transient opening on the ventral side of the developing optic cup, which will close eventually. The failure in closing the optic fissure leads to coloboma, a congenital eye disease that disrupts children's vision significantly, even cause blindness at the most severe situation. At present, the cellular and molecular mechanism governing the optic fissure closure is far from clear, which makes the study of the etiology of coloboma difficult. Through analysis of the detailed cellular process of the optic fissure closure in mice, we noticed that optic fissure closure is a precisely controlled morphogenesis process that involves significant remodeling of cell-cell and cell-ECM (extracellular matrix)interaction. However, currently we know nothing about the matrix metalloproteinase and cytoskeleton regulatory proteins involved in these cell-cell and cell-ECM remodeling, as well as the regulatory mechanisms that control the expression and function of these proteins. In this proposed study, we will start with searching for genes that are specifically expressed in the optic cup progenitor cells surrounding the optic fissure, combine the transcriptome analysis, cell biology, molecular biology, mice and zebrafish genetics to search for genes that execute the fusion process of the optic fissure, and study how they are regulated. Our study will reveal the cellular and molecular mechanisms governing the optic fissure closure, which are the bases for developing strategies to diagnose and treat coloboma.