Identification of genes responsible for glucocorticoid-induced glaucoma

糖皮质激素诱发青光眼基因的鉴定

• 批准号: 8583538
• 负责人: Weiming Mao
• 金额: $ 21.08万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583538
• 关键词: Actins; Affect; Animals; Anterior; Aqueous Humor; Biological; Biological Markers; Blindness; Cattle; Cell Culture Techniques; Cells; Characteristics; Clinical; Data; Development; Disease; Eye; Eye diseases; Gene Expression; Gene Expression Profiling; General Population; Genes; Glaucoma; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Human; Knowledge; Lead; Mediating; Medicine; Mission; Modeling; Molecular Profiling; Ocular Hypertension; Open-Angle Glaucoma; Pathogenesis; Pathway interactions; Patients; Perfusion; Phenotype; Physiologic Intraocular Pressure; Play; Primary Open Angle Glaucoma; Public Health; Receptor Signaling; Reporting; Research; Risk; Role; Sampling; Signal Pathway; Testing; Therapeutic Effect; Tissue Banks; Tissues; Trabecular meshwork structure; Uncertainty; Uveitis; Vision; Work; base; crosslink; diabetic; expectation; gene discovery; in vivo; innovation; macular edema; myocilin; novel; optic nerve disorder; overexpression; response; vector

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.

项目摘要/摘要 糖皮质激素(GC)引起的高眼压(OHT)和青光眼(GIG)发生在30%-40%的普通人群中 人口。易感人群被称为GC反应者，而其他人被称为无反应者。Alt- 尽管这种眼病已经研究了几十年，但人们对这种疾病的认识存在着根本性的差距。 松开机构。因此，这个项目的长期目标是阐明这些途径及其组成。 介导GC诱导的OHT和GIG的小梁网络(TM)中的Nents。本申请的目标是- 目的是确定与GC诱导的OHT和GIG相关的关键TM基因。核心假设是-- 基于GIG是由基因决定的这一事实，Esis是由TM中的一组选定的基因决定的 用于GC诱导的OHT和GIG。这项研究的理论基础是对GIG的理解有助于发展 新的GCs诱发GIG的可能性较小，治疗效果较好。此外，这些知识 GIG将帮助我们了解原发性开角型青光眼，因为它们有广泛的相似性。 在强大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 GC-响应型和非响应型牛TM(BTM)差异表达或调控基因 细胞/组织；以及2)确定(从SA#1中)确定的基因在GC响应性和GC- 诱导性OHT。在第一个目标下，已经构建的牛眼前节灌流培养模型将 用于建立/收集GC响应者和非响应者眼睛的BTM细胞和组织。通过比较- GC应答者和无应答者之间基因表达谱的子代，差异基因 EXPRESS将被选为GIG的候选人。在第二个目标下，SA#1的候选人将被操纵- 在BTM细胞培养和灌流培养的牛眼中检测它们是否介导了GC诱导 生物效应。这个项目意义重大，因为它将阐明决定GC诱导的关键因素 OHT和GIG。这种方法是创新的，因为TM细胞/组织具有明确定义和记录的IOP 对GC的反应将用于基因表达谱分析。最终，这些关键因素的发现将 毫无疑问，这有助于更好地了解这种威胁视力的疾病。它们将作为进一步重新开发的指南。 在人眼和生物标志物中寻找更安全的GC的发展。