Analysis of Glaucoma Gene Interactions

青光眼基因相互作用分析

• 批准号: 6983395
• 负责人: Brian A Link
• 金额: $ 32.93万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983395
• 关键词: alternatives to animals in research; anterior chamber; congenital eye disorder; developmental genetics; developmental neurobiology; disease /disorder etiology; functional /structural genomics; gene interaction; gene mutation; genetic mapping; genetic models; genetic regulation; genetic susceptibility; genetic techniques; glaucoma; intraocular aqueous flow; intraocular pressure; molecular genetics; nonmammalian vertebrate embryology; pathologic process; phenotype; zebrafish

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.

描述（由申请人提供）：拟议的研究的总体目标是了解前部片段发育和青光眼必不可少的基因之间的关系。具体而言，我们将检验以下假设：当突变可以与其他基因座相互作用以促进和影响青光眼的过程时，基因对前部的发育至关重要。青光眼是以视网膜神经节细胞死亡，视神经损伤和视野损失为特征的一组异质性眼疾病。升高的眼压是主要危险因素。在人类基因中已经鉴定出几种突变，导致前节发育不全并导致青光眼。对这些发育性青光眼以及大多数其他形式的青光眼的谱系分析表明，多个遗传基因座共同起作用并影响疾病的进展。但是，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节前节发育并与其他基因座相互作用以引起青光眼的基因。为了实现这一目标，我们将首先彻底评估野生型鱼的前部发育，并评估已知有助于人类青光眼的两个发育重要基因的作用（IMX1B和FOXC1）。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（Bug Eye），该突变（Bug Eye）在纯合时，杂合和杂合时引起前部异常，并因另一个突变而遗传会导致人眼内压力升高，而成人的渐进神经节损失。与胚胎中的详细表型评估同时，将确定关键基因座中的分子遗传缺陷。