Forward Genetics to Identify Complex Gene Interactions Involved in Glaucoma

正向遗传学鉴定青光眼中涉及的复杂基因相互作用

• 批准号: 7935225
• 负责人: Brian A Link
• 金额: $ 47.1万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935225
• 关键词: Address; Adult; Affect; African American; Age-Years; Anatomy; Anterior; Biological Models; Blindness; Cell Death; Complex; DNA Sequence Analysis; Disease; Embryo; Eye; Eye diseases; Fishes; Genes; Genetic; Genetic Screening; Genomics; Glaucoma; Homeostasis; Human; Incidence; Individual; Maps; Measures; Methodology; Mutation; Myopia; Nature; Nucleotides; Orthologous Gene; Patients; Phenotype; Physiologic Intraocular Pressure; Physiology; Prevalence; Primary Open Angle Glaucoma; Reporter; Retinal Ganglion Cells; Retroviridae; Risk; Sampling; Siblings; Signaling Pathway Gene; Testing; Transgenes; Vision; Zebrafish; aged; brass; cell injury; gene interaction; genetic pedigree; human DNA; mutant; prevent; public health relevance; response; tool

DESCRIPTION (provided by applicant): This application is in response to (08) Genomics 09-EY-101: Genomics of complex eye diseases. Using forward genetics in zebrafish and pedigree/patient DNA sequence analysis in humans, we will identify complex genetic interactions that contribute to phenotypes associated with primary open angle glaucoma. The glaucomas are a group of vision impairing diseases characterized by retinal ganglion cell death, and frequently associated with elevated intraocular pressure. Glaucoma is the second leading cause of blindness world-wide, with a prevalence of approximately 1.0% overall. However, specific groups including aged individuals, African-Americans, and those with myopia are at greater risk. For example, for individuals over 40 years of age the incidence of glaucoma is 1.9%. The incidence increases further to 3.5% in people over 70 years of age. The complex nature and limits of traditional genetic approaches in humans and mammalian model systems has prevented the identification of most genes that impact glaucoma. Over the past few years we have developed methodologies and tools in zebrafish to detect and measure glaucoma-associated phenotypes in both larval and aged zebrafish. Zebrafish show similar ocular anatomy and physiology to humans and are highly amenable to large-scale forward genetic screens to identify genes and signaling pathways that affect normal homeostasis or cause disease. In the current study we propose a genetic screen in adult zebrafish to identify mutants that display anterior segment dysgenesis, elevated intraocular pressure, and/or retinal ganglion cell degeneration. We will then use these mutants to identify the causative loci for each mutation. Finally, we will investigate whether any of the genes PUBLIC HEALTH RELEVANCE: The proposal outlines a genetic screen in zebrafish for mutations that result in aged adult onset glaucoma associated phenotypes. The screen takes advantage of an existing zebrafish mutation we recently identified that has non-pathological raised intraocular pressure. This mutation functions as a sensitized background or "pre-disposed condition" that will aid in identifying new mutations that result in blinding degenerations. We will follow this screen by identifying the affected genes and performing a more detailed phenotype characterization for each mutation. Finally, identified genes will be used to address whether othologous loci are affected in human glaucomas.

描述（由申请人提供）：本申请是对(08)基因组学09-EY-101：复杂眼病基因组学的回应。利用斑马鱼的正向遗传学和人类谱系/患者 DNA 序列分析，我们将识别导致与原发性开角型青光眼相关表型的复杂遗传相互作用。青光眼是一组以视网膜神经节细胞死亡为特征的视力损害疾病，并且通常与眼内压升高相关。青光眼是全球第二大致盲眼病，总体患病率约为 1.0%。然而，包括老年人、非裔美国人和近视患者在内的特定群体面临的风险更大。例如，对于40岁以上的人来说，青光眼的发病率为1.9%。 70岁以上人群的发病率进一步增加至3.5%。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阻碍了大多数影响青光眼的基因的鉴定。在过去的几年中，我们开发了斑马鱼的方法和工具来检测和测量幼虫和老年斑马鱼中与青光眼相关的表型。斑马鱼表现出与人类相似的眼部解剖学和生理学，并且非常适合大规模的正向遗传筛选，以识别影响正常体内平衡或引起疾病的基因和信号通路。在当前的研究中，我们提出对成年斑马鱼进行遗传筛查，以鉴定表现出眼前节发育不全、眼内压升高和/或视网膜神经节细胞变性的突变体。然后我们将使用这些突变体来识别每个突变的致病位点。最后，我们将研究是否有任何基因 公共健康相关性：该提案概述了斑马鱼的基因筛查，以查找导致老年青光眼相关表型的突变。该筛查利用了我们最近发现的现有斑马鱼突变，该突变具有非病理性眼内压升高。这种突变起到致敏背景或“预设条件”的作用，有助于识别导致致盲性变性的新突变。我们将通过识别受影响的基因并对每个突变进行更详细的表型表征来进行此筛选。最后，已鉴定的基因将用于解决人类青光眼中的同源基因座是否受到影响。