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）诱导的眼高血压（OHT）和青光眼（GIG）发生在30-40％的一般性中 人口。易感人士称为GC响应者，而其他人则称为非反应者。 alt 霍夫已经研究了这种眼部疾病数十年来，了解疾病存在根本的差距 轻松机制。因此，该项目的长期目标是阐明途径及其组合 介导GC诱导的OHT和GIG的小梁网（TM）中的NENTS。该应用程序的目标 旨在确定负责GC诱导的OHT和GIG的关键TM基因。中央假设 ESI基于GIG是基因确定的事实，是TM中的一组基因是负责 用于GC引起的OHT和演出。这项研究的理由是，对演出的理解有助于发展 新型GC具有较小潜力的诱导演出以及更好的治疗作用。另外，知识 演出将有助于我们理解主要的开角青光眼，因为它们具有广泛的相似性。 在强大的初步数据的指导下，该假设将通过追求两个具体目标来检验：1）确定 在GC响应器和非反应器牛TM（BTM）中差异表达或调节的基因 细胞/组织； 2）确定鉴定的基因（来自SA＃1）在GC响应性和GC-中的作用 诱导的OHT。在第一个目标下，已经建造的牛前部灌注培养模型将 用于从GC响应器和非反应眼中建立/收集BTM细胞和组织。相比 GC反应者和非反应者之间的基因表达谱的儿子，差异化的基因 表达的将被选为演出的候选人。在第二个目标下，SA＃1的候选人将是Manipu- 在BTM细胞培养物和灌注培养的牛眼中均粘以确定它们是否介导GC诱导 生物学效应。该项目很重要，因为它将阐明确定GC诱导的关键因素 OHT和演出。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的反应将用于基因表达分析。最终，发现这些关键因素将 毫无疑问，有助于更好地理解这种威胁视力的疾病。他们将作为进一步重新的指南 在人眼中搜索以及生物标志物，以开发更安全的GC。