Analysis of Glaucoma Gene Interactions

青光眼基因相互作用分析

• 批准号: 7539890
• 负责人: Brian A Link
• 金额: $ 33.1万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539890
• 关键词: Adult; Affect; Anatomy; Anterior; Aqueous Humor; Cell Death; Complex; Development; Developmental Gene; Disease; Disease Progression; Embryo; Evaluation; Eye; Fishes; Gene Expression; Gene Mutation; Genes; Genetic; Glaucoma; Goals; Human; Inherited; Knowledge; Link; Modeling; Molecular Genetics; Mutate; Mutation; Optic Nerve; Phenotype; Physiologic Intraocular Pressure; Regulation; Research; Research Personnel; Retinal Ganglion Cells; Risk Factors; Role; Testing; Visual Fields; Zebrafish; ganglion cell; gene interaction; genetic pedigree; positional cloning

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）：拟议研究的总体目标是了解眼前节发育必需的基因与青光眼之间的关系。具体来说，我们将测试这样的假设：眼前节发育必需的基因在突变时可以与其他基因座相互作用，从而促进和影响青光眼的病程。青光眼是一组异质性眼部疾病，其特征是视网膜神经节细胞死亡、视神经损伤和视野丧失。眼压升高是一个主要危险因素。人类基因中已发现多种突变，这些突变会导致眼前节发育不全并导致青光眼。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，多个基因位点协同作用，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。我们建议使用斑马鱼来识别和研究调节眼前节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，我们将首先彻底评估野生型鱼类的眼前段发育，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育知识来描述一种新的斑马鱼突变（虫眼），当纯合和杂合时，该突变会导致前段异常，并且遗传另一种突变会导致成人眼压升高和进行性神经节细胞丧失。在对胚胎进行详细表型评估的同时，将鉴定关键位点的分子遗传缺陷。