Modulators of Retinal Injury

视网膜损伤的调节剂

基本信息

批准号：
8500956
负责人：
ELDON E GEISERT
金额：
$ 37.5万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8500956
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 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 public health relevance response tool trait translational approach treatment strategy

项目摘要

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（由申请人提供）：绿哥木马是一系列复杂的疾病，所有疾病都具有视网膜神经节细胞（RGC）死亡和失明的最终终点。它们具有各种表型和遗传危险因素，包括眼内压（IOP）升高，中央角膜厚度降低（CCT），轴向长度增加，年龄增加以及视神经头的杯赛比率增加。本项目使用BXD RI小鼠应变集来表征与人青光眼-CCT相关的两种特定的眼表型，以及由于IOP升高而导致的视网膜神经节细胞丧失。这些定量数据将用于定义基因组基因座调节这两种表型。扩展分析将确定基因座中的候选基因以及这些候选基因形成的遗传网络。与Janey Wiggs博士合作，我们将使用双向翻译方法将小鼠中这些表型调节的常见遗传基因座与具有青光眼的人类联系起来。我们的协作组，包括小鼠和人类遗传学专家，已经鉴定出小鼠中的基因组基因座，这些基因素基因座调节了CCT中自然发生的变化，并且还通过实验性增加IOP引起的轴突损失。我们对CCT遗传调节剂的初步分析定义了CHR 13和几个候选基因上的一个重要基因座，其中之一是LYST。在人类中，gwas lyst与青光眼具有显着关联。此外，我们已经确定了CHR 18上的一个重要基因座，该基因座与IOP升高后的轴突丢失有关。该基因座（SMAD2）中的一个基因与人类中正常的青光眼有关联。将小鼠中的基因组分析与人类GWAS研究的数据相结合，使我们的小组能够鉴定两个可能有助于人青光眼的基因（LYST和SMAD2）。我们将扩展这种方法，以暴露与人青光眼有关的小鼠中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中定义与人青光眼相关的不同基因之间的复杂相互作用。