Analysis of Glaucoma Gene Interactions

描述(申请人提供)：青光眼是一组视力受损的疾病，以进行性视神经损害、视网膜神经节细胞死亡和视野丧失为特征。危险因素包括年龄、家族史、眼前段发育不全、眼压升高和高度近视。在人类和哺乳动物模型系统中，传统遗传方法的复杂性和局限性限制了大多数影响青光眼的基因的识别。在之前的资助期间，我们开发了斑马鱼的方法和工具，以检测和研究胚胎和成年斑马鱼的青光眼相关表型。我们还分离出了表现青光眼相关表型的突变株。Bugeye突变就是一个例子，突变鱼表现出眼压升高、高度近视/眼炎、视神经损伤和进行性神经节细胞丢失。在目前的研究中，我们建议进行实验，以探索Bugeye突变体眼睛表型背后的信号通路。此外，我们还将探讨前段的细胞生物学基础和神经元病理。最后，我们将研究我们通过连锁分析确定的一个潜在的抑制突变体，同时还将继续寻找布格耶表型的其他修饰基因。 与公共健康相关：青光眼是美国乃至全世界的一个重大健康问题。由于疾病的复杂性质，对疾病的遗传基础和病理的细胞生物学基础缺乏充分的了解。在这一应用中，我们建议在斑马鱼身上进行实验，以了解这种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.