Identification of genes responsible for glucocorticoid-induced glaucoma

描述（由申请人提供）：30-40%的普通人群发生糖皮质激素（GC）诱导的高眼压（OHT）和青光眼（GIG）。易感者被称为GC反应者，而其他人被称为无反应者。虽然这种眼病已经研究了几十年，但在理解疾病机制方面存在根本性的差距。因此，本项目的长期目标是阐明小梁网（TM）中介导GC诱导的OHT和GIG的途径及其组分。本申请的目的是确定负责GC诱导的OHT和GIG的关键TM基因。基于GIG由遗传决定的事实，中心假设是TM中的一组选择基因负责GC诱导的OHT和GIG。本研究的基本原理是，了解GIG有助于开发新的GCs，其诱导GIG的可能性较小，并且具有更好的治疗效果。此外，知识 GIG将帮助我们了解原发性开角型青光眼，因为它们有着广泛的相似性。在强有力的初步数据的指导下，将通过追求两个特定目标来检验该假设：1）鉴定在GC应答者和非应答者牛TM（BTM）细胞/组织中差异表达或调节的基因; 2）确定鉴定的基因（来自SA#1）在GC应答性和GC诱导的OHT中的作用。在第一个目标下，将使用已经构建的牛眼前节灌注培养模型来建立/收集来自GC应答者和非应答者眼睛的BTM细胞和组织。通过比较GC应答者和非应答者之间的基因表达谱，将选择差异表达的基因作为GIG的候选基因。在第二个目标下，将在BTM细胞培养物和灌注培养的牛眼中操作来自SA#1的候选物，以确定它们是否介导GC诱导的生物学效应。这个项目是有意义的，因为它将阐明决定GC诱导的OHT和GIG的关键因素。该方法具有创新性，因为具有明确定义和记录的对GC的IOP反应的TM细胞/组织将用于基因表达谱分析。最终，这些关键因素的发现无疑将有助于更好地了解这种威胁视力的疾病。它们将作为进一步研究人眼的指南，以及开发更安全GC的生物标志物。

DESCRIPTION (provided by applicant): Glucocorticoid (GC)-induced ocular hypertension (OHT) and glaucoma (GIG) occurs in 30-40% of the general population. The susceptible people are called GC-responders while the others are called non-responders. Although this ocular disease has been studied for decades, there is a fundamental gap in understanding the disease mechanism. Therefore, the long-term goal of this project is to elucidate the pathways and their components in the trabecular meshwork (TM) that mediate GC-induced OHT and GIG. The objective in this application is to determine the key TM genes that are responsible for GC-induced OHT and GIG. The central hypothesis, based on the fact that GIG is genetically determined, is that a select set of genes in the TM is responsible for GC-induced OHT and GIG. The rationale for this study is that the understanding of GIG helps to develop novel GCs with less potential of inducing GIG as well as better therapeutic effects. In addition, the knowledge of GIG will help us to understand primary open angle glaucoma because they share extensive similarities. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) identify the genes that are differentially expressed or regulated in GC-responder and non-responder bovine TM (BTM) cells/tissues; and 2) determine the role of the genes identified (from SA#1) in GC responsiveness and GC-induced OHT. Under the 1st aim, an already constructed bovine anterior segment perfusion culture model will be used to establish/collect BTM cells and tissues from GC-responder and non-responder eyes. By comparison of gene expression profiles between GC-responders and non-responders, the genes that are differentially expressed will be selected as candidates for GIG. Under the 2nd aim, the candidates from SA#1 will be manipulated in BTM cell cultures and perfusion cultured bovine eyes to determine whether they mediate GC-induced biological effects. This project is significant, because it will elucidate the key factors that determine GC-induced OHT and GIG. The approach is innovative, because TM cells/tissues with clearly defined and recorded IOP response to GCs will be used for gene expression profiling. Ultimately, the discovery of these key factors will no doubt help to better understand this vision-threatening disease. They will serve as a guide for further research in the human eye as well as biomarkers for the development of safer GCs.