Identification of genes responsible for glucocorticoid-induced glaucoma

项目概要/摘要 糖皮质激素（GC）诱导的高眼压（OHT）和青光眼（GIG）发生在30 - 40%的一般人群中， 人口易感者被称为GC反应者，而其他人被称为无反应者。替代- 虽然这种眼病已经研究了几十年，但在理解这种疾病方面存在根本性的差距， 缓解机制。因此，本项目的长期目标是阐明这些途径及其组成， 小梁网（TM）中介导GC诱导的OHT和GIG的成分。本申请的目的是- 目的是确定与GC诱导的OHT和GIG相关的关键TM基因。中央hypoth- 基于GIG是由基因决定的这一事实，假设TM中的一组选择性基因负责 GC诱导的OHT和GIG。本研究的基本原理是，对GIG的理解有助于发展 新的GCs诱导GIG的可能性较小，治疗效果更好。此外，知识 GIG将有助于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，这一假设将通过追求两个具体目标来检验：1）确定 在GC应答者和非应答者牛TM（BTM）中差异表达或调节的基因 细胞/组织;和2）确定（来自SA#1）鉴定的基因在GC反应性和GC-1中的作用。 诱导OHT。在第一个目标下，已经构建的牛眼前节灌注培养模型将 用于建立/收集来自GC应答者和非应答者眼睛的BTM细胞和组织。相比之下， GC反应者和非反应者之间的基因表达谱的儿子， 将被选为GIG的候选人。在第二个目标下，来自SA#1的候选人将被操纵- 在BTM细胞培养物和灌注培养的牛眼中进行标记，以确定它们是否介导GC诱导的 生物效应。该项目意义重大，因为它将阐明决定GC诱导的关键因素， OHT和GIG。该方法具有创新性，因为TM细胞/组织具有明确定义和记录的IOP 对GC的响应将用于基因表达谱分析。最终，这些关键因素的发现 无疑有助于更好地了解这种威胁视力的疾病。它们将作为进一步改革的指南。 在人眼中搜索以及生物标志物，以开发更安全的GC。

PROJECT SUMMARY/ABSTRACT 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. Alt- hough this ocular disease has been studied for decades, there is a fundamental gap in understanding the dis- ease mechanism. Therefore, the long-term goal of this project is to elucidate the pathways and their compo- nents in the trabecular meshwork (TM) that mediate GC-induced OHT and GIG. The objective in this applica- tion is to determine the key TM genes that are responsible for GC-induced OHT and GIG. The central hypoth- esis, 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 compari- son 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 manipu- lated 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 re- search in the human eye as well as biomarkers for the development of safer GCs.