Signaling and Gene Interactions Underlying Glaucoma Risk Phenotypes

青光眼风险表型背后的信号传导和基因相互作用

• 批准号: 8879148
• 负责人: Brian A Link
• 金额: $ 37.49万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879148
• 关键词: Adult; Affinity; Age; Alleles; Anterior; Biological; Biological Models; Cell Death; Cells; Complex; Disease; Embryo; Epithelium; Family; Figs - dietary; Fishes; Funding; Genes; Genetic; Genetic Predisposition to Disease; Glaucoma; Goals; Health; Homeostasis; Human; LDL-Receptor Related Protein 2; LDL-Receptor Related Proteins; Methodology; Molecular; Mutation; Myopia; Nature; Neurons; Optic Nerve; Pathogenesis; Pathology; Phenotype; Proteins; Recording of previous events; Retinal Ganglion Cells; Retinoids; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Suppressor Genes; Testing; United States; Vision; Visual Fields; Zebrafish; base; ganglion cell; gene interaction; genetic approach; genetic linkage analysis; high intraocular pressure; mutant; 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. We have 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, 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 that we identified through linkage analysis, while also pursuing the identification of other modifier genes of the bugeye phenotypes.

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。我们已经开发了在斑马鱼中检测和研究胚胎和成年斑马鱼中青光眼相关表型的方法和工具。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识别。

项目成果

Integrin α5/fibronectin1 and focal adhesion kinase are required for lens fiber morphogenesis in zebrafish.

• DOI: 10.1091/mbc.e12-09-0672
• 发表时间: 2012-12
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Hayes JM;Hartsock A;Clark BS;Napier HR;Link BA;Gross JM
• 通讯作者: Gross JM

Lmx1b is required for the glutamatergic fates of a subset of spinal cord neurons.

• DOI: 10.1186/s13064-016-0070-1
• 发表时间: 2016-08-23
• 期刊: Neural development
• 影响因子: 3.6
• 作者: Hilinski WC;Bostrom JR;England SJ;Juárez-Morales JL;de Jager S;Armant O;Legradi J;Strähle U;Link BA;Lewis KE
• 通讯作者: Lewis KE

Morphogenesis of the anterior segment in the zebrafish eye.

• DOI: 10.1186/1471-213x-5-12
• 发表时间: 2005-06-28
• 期刊: BMC developmental biology
• 作者: Soules KA;Link BA
• 通讯作者: Link BA

The visual system of zebrafish and its use to model human ocular diseases.

• DOI: 10.1002/dneu.20919
• 发表时间: 2012-03
• 期刊: Developmental neurobiology
• 影响因子: 3
• 作者: Gestri G;Link BA;Neuhauss SC
• 通讯作者: Neuhauss SC