Analysis of Glaucoma Gene Interactions

描述(由申请人提供)：拟议研究的总体目标是了解眼前段发育所必需的基因与青光眼的关系。具体地说，我们将测试这一假设，即对眼前段发育至关重要的基因，当发生突变时，可以与其他基因座相互作用，促进和影响青光眼的进程。青光眼是一组以视网膜神经节细胞死亡、视神经损伤和视野丧失为特征的异质性眼病。眼压升高是一个主要的危险因素。已经在人类基因中发现了几个突变，这些突变会导致眼前节发育不良，并导致青光眼。对这些发育性青光眼以及大多数其他形式的青光眼的系谱分析表明，多个遗传位点协同作用导致并影响疾病的进展。然而，其中许多相关基因的身份尚不清楚。我们建议使用斑马鱼来识别和研究调控眼前节发育并与其他基因位点相互作用导致青光眼的基因。为了实现这一目标，我们将首先彻底评估野生型鱼类的前节发育，并评估两个已知与人类青光眼有关的发育重要基因(Imx1b和foxC1)的作用。接下来，我们将应用我们的发育知识来描述一种新的斑马鱼突变(虫眼)，这种突变在纯合和杂合时会导致眼前节异常，当与另一种突变一起遗传时会导致成人眼压升高和进行性神经节细胞丢失。在对胚胎进行详细的表型评估的同时，关键基因座上的分子遗传缺陷将被识别出来。

DESCRIPTION (provided by applicant): The overall goal of the proposed research is to understand the relationships between genes essential for anterior segment development and glaucoma. Specifically, we will test the hypothesis that genes essential for anterior segment development, when mutated can interact with other loci to promote and affect the course of glaucoma. The glaucomas are a heterogeneous group of ocular disorders characterized by retinal ganglion cell death, optic nerve damage and visual field loss. Elevated intraocular pressure is a major risk factor. Several mutations have been identified in human genes that result in anterior segment dysgenesis and contribute to glaucoma. Pedigree analysis of these developmental glaucomas, as well as most other forms of glaucoma, indicate that multiple genetic loci act in concert to cause and affect the progression of the disease. However, the identities of many of these relevant genes are not known. We propose to use zebrafish to identify and study genes which regulate anterior segment development and interact with other loci to cause glaucoma. To accomplish this objective, we will first thoroughly evaluate anterior segment development in wild type fish and assess the roles of two developmentally important genes known to contribute to glaucoma in humans (Imx1b and foxC1). Next we will apply our knowledge of development to characterize a new zebrafish mutation (bug eye) which causes anterior segment anomalies when homozygous and when heterozygous and inherited with another mutation causes elevated intraocular pressure and progressive ganglion cell loss in adults. Concurrent with detailed phenotype evaluation in embryos, the molecular genetic defects in the critical loci will be identified.