Analysis of Glaucoma Gene Interactions

描述（由申请人提供）：青光眼是一组视力损害疾病，其特征为进行性视神经损伤、视网膜神经节细胞死亡和视野丧失。危险因素包括年龄、家族史、眼前节发育不全、眼内压升高和高度近视。人类和哺乳动物模型系统中传统遗传方法的复杂性质和限制了对影响青光眼的大多数基因的鉴定。在上一个资助期，我们开发了斑马鱼的方法和工具，以检测和研究胚胎和成年斑马鱼中与斑马鱼相关的表型。我们还分离出了显示出肉瘤相关表型的突变体。bugeye突变是一个例子，因为突变鱼显示出眼内压升高、高度近视/牛眼症、视神经损伤和进行性神经节细胞损失。在目前的研究中，我们提出的实验，探索信号通路的基础上的眼睛表型的bugeye突变体。此外，我们将探讨眼前节和神经元病理的细胞生物学基础。最后，我们将研究一个潜在的抑制突变，我们通过连锁分析确定，同时也追求的bugeye表型的其他修饰基因的鉴定。 公共卫生相关性：青光眼是美国和世界普遍存在的重大健康问题。由于疾病的复杂性，对疾病的遗传基础和病理学的细胞生物学基础的知识缺乏充分的理解。在这项应用中，我们提出了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。

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.