Identification of genes responsible for glucocorticoid-induced glaucoma

糖皮质激素诱发青光眼基因的鉴定

基本信息

批准号：
8720007
负责人：
Weiming Mao
金额：
$ 17.76万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720007
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

项目摘要

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.

描述（由申请人提供）：糖皮质激素（GC）诱导的眼高血压（OHT）和青光眼（GIG）发生在30-40％的一般人群中。易感人士称为GC响应者，而其他人则称为非反应者。尽管已经研究了这种眼部疾病数十年，但了解疾病机制存在根本的差距。因此，该项目的长期目标是阐明介导GC引起的OHT和GIG的小梁网（TM）中的途径及其组成部分。本应用程序的目的是确定负责GC引起的OHT和GIG的关键TM基因。基于GIG是遗传确定的事实的中心假设是，TM中的一组基因组成了GC诱导的OHT和GIG。这项研究的理由是，对演出的理解有助于开发具有较小潜力以及更好的治疗作用潜力的新型GC。另外，知识演出将帮助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，将通过追求两个具体目的来检验该假设：1）确定在GC响应器和非反应器牛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响应性和GC诱导的OHT中的作用。在第一个目标下，已经构建的牛前节灌注培养模型将用于从GC响应者和非反应者眼中建立/收集BTM细胞和组织。通过比较GC反应者和非反应者之间的基因表达谱，将选择差异表达的基因作为GIG的候选者。在第二个目标下，SA＃1的候选者将在BTM细胞培养物和灌注培养的牛眼中进行操纵，以确定它们是否介导GC诱导的生物学作用。该项目很重要，因为它将阐明决定GC引起的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IOP响应的TM细胞/组织将用于基因表达分析。最终，这些关键因素的发现无疑将有助于更好地理解这种威胁性的疾病。他们将作为人眼中进一步研究的指南以及生物标志物，以开发更安全的GC。