Analysis of Glaucoma Gene Interactions

青光眼基因相互作用分析

• 批准号: 7791051
• 负责人: Brian A Link
• 金额: $ 37.25万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791051
• 关键词: Adult; Affinity; Age; Alleles; Anterior; Biological; Biological Models; Cell Death; Cells; Complex; Disease; Embryo; Epithelium; Eye; Family history of; Figs - dietary; Fishes; Funding; Genes; Genetic; Glaucoma; Health; Human; Knowledge; LDL-Receptor Related Protein 2; LDL-Receptor Related Proteins; Methodology; Mutation; Myopia; Nature; Neurons; Optic Nerve; Pathogenesis; Pathology; Pathway interactions; Phenotype; Proteins; Retinal Ganglion Cells; Retinoids; Risk Factors; Role; Signal Pathway; Signal Transduction; Suppressor Genes; Tretinoin; Vision; Visual Fields; Zebrafish; base; disease characteristic; ganglion cell; gene interaction; genetic linkage analysis; high intraocular pressure; mutant; public health relevance; receptor; receptor mediated endocytosis; research study; tool

DESCRIPTION (provided by applicant): The glaucomas are a group of vision impairing diseases characterized by progressive optic nerve damage, retinal ganglion cell death, and visual field loss. Risk factors include age, family history, anterior segment dysgenesis, elevated intraocular pressure, and high myopia. The complex nature and constraints of traditional genetic approaches in humans and mammalian model systems has limited the identification of most genes that impact glaucoma. In the previous funding period we developed methodologies and tools in zebrafish to detect and study glaucoma-associated phenotypes in both embryonic and adult zebrafish. We have also isolated mutants that display glaucoma-associated phenotypes. The bugeye mutation is an example in that mutant fish show elevated intraocular pressure, high myopia/buphthalmia, optic nerve damage and progressive ganglion cell loss. In the current study we propose experiments to explore the signaling pathways that underlie the ocular phenotypes of bugeye mutants. In addition, we will explore the cell biological basis of the anterior segment and neuronal pathology. Finally, we will study one potential suppressor mutant which we identified through linkage analysis, while also pursuing the identification of other modifier genes of the bugeye phenotypes. PUBLIC HEALTH RELEVANCE: Glaucoma is a significant health problem for the US and world in general. Due to the complex nature of the disease, a full understanding of the genetic basis of the disease and knowledge of the cell biological underpinnings of the pathology is lacking. In this application, we propose experiments in zebrafish to understand the genetic basis and mechanisms of core characteristics of the disease.

描述（由申请人提供）：绿哥木马是一组视力损害，其特征是以进行性视神经损伤，视网膜神经节细胞死亡和视野损失为特征。危险因素包括年龄，家族病史，前部失调，眼内压力升高和近视高。人类和哺乳动物模型系统中传统遗传方法的复杂性质和约束限制了影响青光眼的大多数基因的鉴定。在上一个资金期间，我们开发了斑马鱼的方法和工具，以检测和研究胚胎和成人斑马鱼的青光眼相关表型。我们还具有显示青光眼相关表型的分离突变体。 Bugeye突变是一个例子，即突变鱼显示出升高的眼内压，高近视/buphthalmia，视神经损伤和进行性神经节细胞损失。在当前的研究中，我们提出了实验，以探索Bugeye突变体眼表型的信号通路。此外，我们将探索前段和神经元病理的细胞生物学基础。最后，我们将研究一种潜在的抑制突变体，我们通过连锁分析确定，同时还追求了Bugeye表型的其他修饰基因的鉴定。 公共卫生相关性：青光眼是美国和整个世界的重大健康问题。由于疾病的复杂性，缺乏对疾病的遗传基础和病理生物学基础知识的全面理解。在此应用中，我们建议在斑马鱼中进行实验，以了解疾病核心特征的遗传基础和机制。