Modulators of Retinal Injury

视网膜损伤的调节剂

• 批准号: 8842635
• 负责人: ELDON E GEISERT
• 金额: $ 38.09万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842635
• 关键词: Accounting; Affect; Age; Axon; Bioinformatics; Biological; Biological Markers; Biological Models; Blindness; CHS1 gene; Candidate Disease Gene; Cell Death; Collaborations; Companions; Complex; Control Locus; Cornea; Data; Development; Disease; Eye; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genomics; Glaucoma; Grant; Health; Human; Human Genetics; Human Genome; Injury; Length; Link; MADH2 gene; Magnetism; Maps; Measurement; Measures; Microspheres; Modeling; Molecular; Molecular Genetics; Monitor; Mouse Strains; Mus; Optic Disk; Optic Nerve; Outcome; Patients; Phenotype; Physiologic Intraocular Pressure; Predisposition; Resources; Retinal; Retinal Ganglion Cells; Risk; Risk Factors; Sampling; Series; Severities; Statistical Models; Testing; Thick; Trabecular meshwork structure; Variant; anterior chamber; base; cohort; ganglion cell; genetic analysis; genetic risk factor; genome wide association study; mouse model; normotensive; novel; prevent; response; tool; trait; translational approach; treatment strategy

DESCRIPTION (provided by applicant): The glaucomas are a complex series of diseases, all of which have the eventual endpoint of retinal ganglion cell (RGC) death and blindness. They have diverse phenotypic and genetic risk factors including elevated intraocular pressure (IOP), decreased central corneal thickness (CCT), increased axial length, increased age, and increased cup-to-disc ratio of the optic nerve head. The present project uses the BXD RI mouse strain set to characterize two specific ocular phenotypes associated with human glaucoma - CCT and the loss of retinal ganglion cells due to elevation of IOP. These quantitative data will be used to define genomic loci modulating these two phenotypes. An extended analysis will identify candidate genes within the loci and also genetic networks formed by these candidate genes. In collaboration with Dr. Janey Wiggs, we will use a bidirectional translational approach to link common genetic loci modulating these phenotypes in the mouse to humans with glaucoma. Our collaborative group, including experts in mouse and human genetics, has already identified genomic loci in the mouse that modulate naturally occurring variation in CCT and also axonal loss induced by experimentally increased IOP. Our preliminary analysis of genetic modulators of CCT defines one significant locus on Chr 13 and several candidate genes, one of which is Lyst. In the human GWAS LYST has a significant association with glaucoma. In addition we have identified one significant locus on Chr 18 that is associated with axon loss following elevation of IOP. One gene in this locus (Smad2) has an association with normotensive glaucoma in humans. Combining our genomic analysis in the mouse with data from the human GWAS studies has allowed our group to identify two genes (LYST and SMAD2) that may contribute to human glaucoma. We will expand this approach to expose additional candidate genes and gene networks in the mouse related to human glaucoma. These studies will also allow us to define in the mouse the complex interactions between different genes associated with human glaucoma.

描述(申请人提供)：青光眼是一系列复杂的疾病，所有这些疾病的最终终点都是视网膜神经节细胞(RGC)死亡和失明。它们有不同的表型和遗传危险因素，包括高眼压(IOP)、中央角膜厚度(CCT)降低、眼轴长度增加、年龄增加和视神经头杯盘比增加。本项目使用BXD RI小鼠品系SET来表征与人类青光眼相关的两种特殊的眼部表型-CCT和由于眼压升高而导致的视网膜神经节细胞丢失。这些定量数据将被用来定义调节这两种表型的基因组座位。扩展分析将确定这些基因座内的候选基因，以及由这些候选基因组成的遗传网络。在与Janey Wiggs博士的合作中，我们将使用双向翻译方法将调节小鼠这些表型的常见遗传位点与患有青光眼的人类联系起来。我们的合作小组，包括小鼠和人类遗传学专家，已经在小鼠中确定了调节CCT自然发生的变异和实验中眼压升高导致的轴突丢失的基因组基因座。我们对CCT的遗传调节因子的初步分析确定了Chr13上的一个重要基因和几个候选基因，其中之一是Lyst。在人类的青光眼中，Lyst与青光眼有显著的相关性。此外，我们还在Chr18上发现了一个与眼压升高后轴突丢失相关的重要基因座。该基因座的一个基因(Smad2)与人类正常血压青光眼有关。结合我们在小鼠身上的基因组分析和来自人类GWAS研究的数据，我们的团队已经识别出可能导致人类青光眼的两个基因(Lyst和Smad2)。我们将扩展这一方法，以揭示小鼠中与人类青光眼相关的其他候选基因和基因网络。这些研究还将使我们能够在小鼠身上确定与人类青光眼相关的不同基因之间的复杂相互作用。