Retinal gene expression changes in glaucoma

描述(申请人提供)：青光眼是一种以退行性视神经病变为特征的疾病家族，通常与LOP升高和视网膜神经节细胞丢失有关。尽管最近在识别与青光眼相关的基因方面取得了进展，但我们对青光眼的病理生理学的了解仍然有限。 该项目的长期目标是确定导致青光眼视网膜病理发展的分子机制。为了实现这一目标，将利用微阵列基因分析来确定不同年龄(3到18个月)的小鼠(包括青光眼和非青光眼小鼠)整个视网膜的差异基因表达。此外，将使用相同的方法确定老年青光眼动物(15至18个月龄)视网膜不同程度RGC丢失区域之间的差异基因表达。视网膜基因的表达也将与青光眼动物的LOP暴露史相关。所有的微阵列分析结果将在RNA和蛋白质水平上得到确认。 通过初步实验，已经确定了一些随着青光眼视网膜病变进展而表达变化的基因。该项目还将调查其中两个基因铜蓝蛋白(Cp)和补体成分1q(C1q)的表达变化在青光眼中是否起到有益/保护或有害/破坏性的作用。这将通过在DBA/2青光眼背景下产生携带这两个基因的敲除突变的同源动物来实现。在实验性灵长类青光眼和青光眼患者的档案组织材料中，cp和C1q蛋白表达水平的上调也将通过免疫组织化学得到证实。 该项目的完成将增加我们对视网膜内参与青光眼发病机制的分子通路的了解，并可能为开发新的治疗方法识别新的靶点。

DESCRIPTION (provided by applicant): Glaucoma is a family of diseases characterized by degenerative optic neuropathy usually related to elevation of lOP and retinal ganglion cells loss. Despite recent advances in identifying genes related to glaucoma our understanding of the pathophysiology of the disease is still limited. The long-term objective of this project is to determine the molecular mechanisms leading to the development of retinal pathology in glaucoma. To achieve this goal, differential gene expression in whole retina of mice (both glaucomatous and non-glaucomatous) of various ages (from 3 to 18 months of age) will be determined using microarray gene analysis. In addition, differential gene expression among areas of the retina with various degrees of RGC loss in aged glaucomatous animals (15 to 18 months of age) will be determined using the same methodology. Retinal gene expression will also be correlated to the lOP exposure history in glaucomatous animals. All microarray analysis results will be confirmed at the RNA as well as the protein level. Through preliminary experiments, a number of genes whose expression changes with the progression of glaucomatous retinal pathology have already been identified. This project will also investigate whether changes in expression of two of these genes, ceruloplasmin (cp) and complement component 1q (C1q), have a beneficial/protective or detrimental/destructive role in glaucoma. This will be achieved by generating congenic animals in the DBA/2 glaucomatous background that carry knockout mutations in these two genes. The up-regulation in the level of expression of the cp and C1q proteins will also be confirmed in archival tissue material from experimental primate glaucoma and patients with glaucoma by immunohistochemistry. Completion of this project will increase our understanding of the molecular pathways within the retina involved in the pathogenesis of glaucoma and might allow the identification of novel targets for development of new therapeutic approaches.