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Molecular mechanisms in steroid-induced glaucoma.

类固醇诱发青光眼的分子机制。

基本信息

批准号：
8268458
负责人：
Oscar A Candia
金额：
$ 48.73万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

项目摘要

Glucocorticosteroids are known to cause intraocular pressure (IOP) elevation in humans. This induced ocular hypertension can lead to glaucomatous visual loss. Steroid-induced glaucoma has over the past few years become more prevalent as many posterior pole conditions are increasingly been treated with potent, long-lasting steroid preparations. Steroid-induced open angle glaucoma is caused by a decrease of trabecular meshwork (TM) outflow facility. Cellular and molecular mechanisms underlying this decrease in outflow facility have been studied in tissue and/or organ culture. However, despite significant advances to our understanding of this disease, we still do not fully understand the molecular mechanisms that lead to steroid induced decrease in facility and the resulting IOP elevation. Over the past few years we have developed two animal models (bovine and ovine) for the study of steroid-induced glaucoma in-vivo and have used one of them to gain some insight into the pathogenesis of the disease. In this project we propose to use the ovine steroid-induced IOP elevation model to dissect the molecular mechanisms of this disease. Our overall hypothesis is that steroid-induced changes of gene and protein expression in the trabecular meshwork (TM) lead to changes in the outflow pathways which ultimately cause a reduction in outflow facility and IOP elevation. We thus propose the following specific aims: 1. To define the role of key genes in a number of inter-connecting networks in steroid induced IOP elevation. Our hypothesis is that these closely linked gene networks mediate the steroid-induced changes in facility and IOP. Thus specific perturbation of these networks will ameliorate or prevent the development of steroid- induced IOP elevation. 2. To study the time-course of gene expression changes that occur in the TM during the development of steroid-induced IOP elevation. Our hypothesis predicts that a small set of genes that belong to a limited number of networks are the initial response to steroid therapy and that changes in their expression ultimately causes changes in the trabecular meshwork that lead to a reduction in outflow facility and IOP elevation. 3. To detect (by proteomic analysis) protein changes that occur during the development of steroid-induced IOP elevation. Our hypothesis is that post-translational modifications (like phosphorylation or glycosylation) modify the activity of key molecules in pathways that affect the development of steroid-induced IOP elevation and the onset of glaucoma. This project is expected to define targets for pharmacologic intervention in steroid-induced glaucoma. In addition, and because of the similarities of steroid-induced with chronic open angle glaucoma, we expect that knowledge gained during this project will help to elucidate some of the pathophysiology of the latter condition as well.

已知糖皮质激素会导致人类眼内压（IOP）升高。该感应高眼压可导致青光眼性视力丧失。类固醇引起的青光眼在过去的几年里随着许多后极病症越来越多地用有效的，长效类固醇制剂。类固醇诱导的开角型青光眼是由于小梁网（TM）流出减少引起的设施。已经研究了流出设施减少的细胞和分子机制，组织和/或器官培养。然而，尽管我们对这种疾病的了解取得了重大进展，但我们仍然尚不完全了解导致类固醇诱导的灵活性降低的分子机制，导致IOP升高。在过去的几年里，我们已经开发了两种动物模型（牛和羊）用于研究类固醇诱导的青光眼在体内，并使用其中之一，以获得一些深入了解的发病机制，疾病在这个项目中，我们建议使用绵羊类固醇诱导的IOP升高模型来解剖这种疾病的分子机制。我们的总体假设是，类固醇诱导的基因和小梁网（TM）中的蛋白表达导致流出途径的变化，导致流出道功能降低和IOP升高。因此，我们提出以下具体目标： 1.目的：明确类固醇诱导的眼压升高中一些相互连接网络中的关键基因的作用。我们的假设是，这些紧密相连的基因网络介导了类固醇诱导的灵活性变化， IOP。因此，这些网络的特定扰动将改善或防止类固醇的发展。诱导IOP升高。 2.为了研究在发育过程中TM中发生的基因表达变化的时间过程，类固醇诱导的IOP升高。我们的假设预测，一小部分基因属于一个有限的许多网络是对类固醇治疗的最初反应，并且最终改变它们的表达引起小梁网的变化，导致流出功能降低和IOP升高。 3.检测（通过蛋白质组学分析）类固醇诱导的发育过程中发生的蛋白质变化眼压升高。我们的假设是，翻译后修饰（如磷酸化或糖基化）改变影响类固醇诱导的IOP升高发展的途径中关键分子的活性和青光眼的发病。该项目有望确定类固醇诱导的青光眼的药物干预目标。此外，由于类固醇诱导的慢性开角型青光眼的相似性，我们预期在这个项目中获得的知识将有助于阐明后者的一些病理生理学条件也。