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前段发育所需基因与青光眼之间的关系。具体来说，我们将验证前节发育所必需的基因，当突变时，可以与其他基因座相互作用，促进和影响青光眼的病程。青光眼是一种异质性的眼部疾病，以视网膜神经节细胞死亡、视神经损伤和视野丧失为特征。眼压升高是主要的危险因素。在人类基因中已经发现了一些突变，这些突变会导致前段发育不良并导致青光眼。这些发育性青光眼的谱系分析，以及大多数其他形式的青光眼，表明多个遗传位点协同作用，导致和影响疾病的进展。然而，许多相关基因的身份尚不清楚。我们建议利用斑马鱼来鉴定和研究调节前段发育并与其他基因座相互作用导致青光眼的基因。为了实现这一目标，我们将首先全面评估野生型鱼类的前段发育，并评估两个已知对人类青光眼有贡献的重要基因（Imx1b和foxC1）的作用。接下来，我们将运用我们的发育知识来描述一种新的斑马鱼突变（虫眼），当纯合子和杂合子并遗传另一种突变导致成人眼压升高和进行性神经节细胞丢失时，这种突变会导致前段异常。在胚胎中进行详细的表型评估的同时，将确定关键位点的分子遗传缺陷。

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.