Analysis of Glaucoma Gene Interactions

描述（申请人提供）：青光眼是一组以进行性视神经损伤、视网膜神经节细胞死亡和视野丧失为特征的视力损害疾病。危险因素包括年龄、家族史、前段发育不良、眼压升高和高度近视。人类和哺乳动物模型系统中传统遗传方法的复杂性和局限性限制了大多数影响青光眼的基因的鉴定。在之前的资助期内，我们在斑马鱼中开发了方法和工具，以检测和研究胚胎和成年斑马鱼的青光眼相关表型。我们也分离出青光眼相关表型的突变体。bugeeye突变就是一个例子，突变鱼表现为眼压升高，高度近视/眼浅，视神经损伤和进行性神经节细胞丢失。在目前的研究中，我们提出的实验，以探索信号通路的基础上的眼突变表型。此外，我们将探讨前节的细胞生物学基础和神经病理学。最后，我们将研究一个潜在的抑制突变，我们通过连锁分析鉴定，同时也追求鉴定其他修饰基因的巨眼表型。

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.