Modulators of Retinal Injury

描述（申请人提供）：青光眼是一种复杂的系列疾病，其最终终点均为视网膜神经节细胞（RGC）死亡和失明。他们有不同的表型和遗传危险因素，包括眼压升高（IOP），角膜中央厚度下降（CCT），轴长增加，年龄增加，视神经头杯盘比增加。本项目使用BXD RI小鼠品系来表征与人类青光眼相关的两种特定眼部表型- CCT和由于IOP升高导致的视网膜神经节细胞损失。这些定量数据将用于定义调节这两种表型的基因组位点。进一步的分析将确定位点内的候选基因，以及由这些候选基因形成的遗传网络。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青光眼患者联系起来。我们的合作小组，包括小鼠和人类遗传学专家，已经确定了小鼠的基因组位点，这些位点调节自然发生的CCT变异和实验性IOP增加引起的轴突损失。我们对CCT遗传调节因子的初步分析确定了Chr 13上的一个重要位点和几个候选基因，其中一个是Lyst。在人类GWAS中，LYST与青光眼有显著的相关性。此外，我们还在Chr 18上发现了一个与IOP升高后轴突损失相关的重要位点。该基因座中的一个基因（Smad2）与人类常压青光眼有关。将小鼠基因组分析与人类GWAS研究数据相结合，使我们的研究小组确定了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中确定与人类青光眼相关的不同基因之间的复杂相互作用。

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.