A bovine eye model for steroid-induced glaucoma

描述(申请人提供)：已知糖皮质激素可引起易感人群的眼压升高，从而导致青光眼视神经病变。激素性青光眼在眼压升高机制和视神经病变方面与原发性开角型青光眼相似。一些导致眼压升高的细胞和分子机制已经在组织和/或器官培养中进行了研究，但还没有在体内进行。因此，一个可靠的类固醇诱导的青光眼动物模型将是一个非常有价值的体内系统，用于测试关于这些机制的特定假说。我们发现局部应用皮质类固醇4周以上的牛眼眼压显著升高。该物种对类固醇反应的一致性，加上牛眼的大小和与人眼的相似之处，使其成为类固醇诱导青光眼的理想动物模型。作为确定这一模式是否适用于未来研究的第一步，我们提议进行调查，以实现以下三个具体目标： 1.确定与青光眼相关的主要结构的组织病理学变化 观察激素性眼压升高过程中的视网膜、视网膜和视神经头(ONH)的变化，并确定每种变化与眼压升高的程度和持续时间的相关性。 2.构建激素性高眼压不同时间点TM、视网膜和ONH差异表达基因文库。这些文库将在未来筛选与类固醇诱导的眼压升高有关的新基因，以及当皮质类固醇升高眼压时可能涉及视网膜和ONH反应的基因。 3.应用基因芯片技术研究激素性眼压升高过程中特定时间点TM、视网膜和ONH的差异表达基因。这些变化的确定将使我们能够潜在地确定导致青光眼病理发展的分子事件序列。

DESCRIPTION (provided by applicant): Glucocorticosteroids are known to cause intraocular pressure (IOP) elevation in susceptible individuals that can lead to glaucomatous optic neuropathy. Steroid-induced glaucoma resembles primary open angle glaucoma in the mechanism of IOP elevation and in the optic neuropathy. Some of the cellular & molecular mechanisms leading to IOP elevation have been studied in tissue and/or organ culture but not in vivo. Thus a reliable animal model of steroid-induced glaucoma would be extremely valuable as an in vivo system for testing specific hypotheses about these mechanisms. We have found that IOP significantly increases in bovine eyes treated topically with corticosteroids for more than 4 weeks. The consistency of the steroid response in this species, together with the size of the bovine eye and its similarities to the human eye make it an ideal animal model for steroid-induced glaucoma. As the first steps towards establishing the suitability of this model for future studies, we propose an investigation to achieve the following three specific aims: 1. To determine the histopathological changes that occur in major structures associated with glaucoma (TM, retina and optic nerve head (ONH)) during the course of steroid-induced IOP elevation in the bovine eye and to determine the correlation of each change with the level and duration of IOP elevation. 2. To generate cDNA libraries of differentially expressed genes in the TM, retina and ONH at various time points during the steroid-induced IOP elevation. Such libraries will be screened in the future for novel genes that are involved in steroid-induced IOP elevation as well as genes that may be involved in the response of the retina and ONH when IOP is elevated by corticosteroids. 3. To determine differentially expressed genes in the TM, retina and ONH at specific time points during the steroid-induced IOP elevation using microarrays. Determination of these changes will allow us to potentially determine the sequence of molecular events responsible for the development of glaucomatous pathology.