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节发育和青光眼所必需的基因之间的关系。具体来说，我们将测试的假设，眼前节发育所必需的基因，突变时可以与其他位点相互作用，以促进和影响青光眼的过程。青光眼是一组异质性的眼部疾病，其特征在于视网膜神经节细胞死亡、视神经损伤和视野丧失。眼内压升高是一个主要的危险因素。已经在人类基因中鉴定出导致眼前节发育不全并导致青光眼的几种突变。这些发育性青光眼以及大多数其他形式的青光眼的谱系分析表明，多个遗传位点共同作用，导致并影响疾病的进展。然而，许多这些相关基因的身份是未知的。我们建议使用斑马鱼来识别和研究调节眼前节发育的基因，并与其他位点相互作用，导致青光眼。为了实现这一目标，我们将首先彻底评估野生型鱼类的眼前节发育，并评估已知导致人类青光眼的两个发育重要基因（Imx1b和foxC1）的作用。接下来，我们将应用我们的发展知识来表征一种新的斑马鱼突变（虫眼），当纯合子和杂合子时会导致前段异常，并且与另一种突变一起遗传会导致成人眼内压升高和进行性神经节细胞丢失。在胚胎中进行详细的表型评价的同时，将鉴定关键基因座中的分子遗传缺陷。

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.