The Functional Role of Decorin in Glaucoma

核心蛋白聚糖在青光眼中的功能作用

• 批准号: 357014458
• 负责人: Professor Dr. Rudolf Fuchshofer
• 金额: --
• 依托单位: Lehrstuhl für Humananatomie und Embryologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/357014458?language=en
• 关键词: Functional; Role; Decorin; Glaucoma

Primary open angle glaucoma (POAG) is one of the leading causes of blindness worldwide. The main risk factor is an elevated intraocular pressure (IOP), which leads to irreversible damage of the optical nerve head. Changes in the extracellular matrix (ECM) of the trabecular meshwork together with an enhanced contractility of cells in the juxtacanalicular trabecular meshwork (JCT) and Schlemm´s canal (SC) are decisive factors in generating the abnormally high IOP. The molecular causes for the changes of the TM outflow pathways in POAG are incompletely understood, but there is strong evidence that alterations in the homeostatic balance of Transforming growth factor (TGF)-beta signaling in the eye are involved. TGF-beta signaling is involved in a broad variety of cellular processes. In the eye, it serves an immunomodulatory role that is necessary for the ocular immune privilege. Prompted by the assumption that there is need for a tight regulation of TGF-beta signaling, which might be compromised in POAG, we focused our research in recent years on the identification of endogenous antagonists of TGF-beta signaling in the eye and on that of downstream mediators of TGF-beta signaling, which might itself cause or contribute to an increased outflow resistance in POAG. In preliminary work, we identified the small leucine-rich proteoglycan Decorin (DCN) as a promising candidate molecule to antagonize signaling of TGF-beta in the eye. DCN were drastically reduced in the outflow tissues of POAG patients and initial data showed that DCN deficient mice have an increased IOP with a severe loss of axons in the optic nerve.Our application is based on the overall hypothesis that DCN is part of a critical signaling system in the eye that is essential to prevent the onset and the progression of POAG. The objective of the planed project is to clarify the functional role of DCN in those ocular tissues and cells that are directly affected in POAG, namely the cells of the TM outflow pathways, the retinal ganglion cells (RGC), and the cells of the ONH. We expect to obtain important information about the interaction of regulatory mechanisms that are involved in ECM turnover, and the modulation of cellular contractility in TM outflow tissues and ONH. Furthermore, we expect to gain deeper insights in mechanisms that are required for homeostasis of RGC somata and their axons including reactive changes in astrocytes, microglia and Müller cells. We trust that the results of the project will provide new information with the distinct potential to lead to new therapeutic strategies preventing the onset and the progression of POAG.

原发性开角型青光眼(POAG)是世界范围内致盲的主要原因之一。主要危险因素是眼压升高，导致视神经头不可逆转的损害。小梁网细胞外基质的改变以及近侧小梁网和Schlemm‘S管细胞收缩能力的增强是引起异常高眼压的决定性因素。POAG中TM流出通路改变的分子原因尚不完全清楚，但有强有力的证据表明，眼内转化生长因子-β信号的动态平衡改变与此有关。转化生长因子-β信号参与了多种细胞过程。在眼睛中，它起着免疫调节的作用，这是眼睛免疫特权所必需的。由于假设有必要严格调控转化生长因子-β信号转导，而这一点在开角型青光眼中可能受到影响，我们在最近几年的研究集中在眼部内源性转化生长因子-β信号的拮抗剂以及转化生长因子-β信号的下游介导物，它们本身可能导致或促成开角型青光眼流出阻力的增加。在前期工作中，我们确定富含亮氨酸的蛋白多糖核心蛋白(DCN)是一种有希望的候选分子，可以拮抗眼睛中的转化生长因子-β信号。在POAG患者的流出组织中，DCN显著减少，初步数据显示，DCN缺乏的小鼠眼压升高，视神经轴突严重丧失。我们的应用基于这样一个总体假设，即DCN是眼睛中关键信号系统的一部分，该系统对于防止POAG的发生和发展至关重要。该计划的目标是阐明DCN在POAG中直接受影响的眼组织和细胞中的功能作用，即TM流出通路细胞、视网膜神经节细胞(RGC)和ONH细胞。我们期望获得与细胞外基质周转有关的调节机制相互作用的重要信息，以及TM流出组织和ONH中细胞收缩的调节。此外，我们希望对RGC胞体及其轴突的稳态所需的机制有更深入的了解，包括星形胶质细胞、小胶质细胞和Müler细胞的反应性变化。我们相信，该项目的结果将提供新的信息，具有明显的潜力，导致新的治疗策略，防止POAG的发生和发展。