The Functional Role of Decorin in Glaucoma

原发性开角型青光眼（POAG）是全球致盲的主要原因之一。主要的危险因素是眼压升高，导致视神经头的不可逆损伤。小梁网细胞外基质（ECM）的改变以及关节旁小梁网（JCT）和施莱姆管（SC）细胞收缩性的增强是产生异常高眼压的决定性因素。POAG中TM流出通路变化的分子原因尚不完全清楚，但有强有力的证据表明，眼睛中转化生长因子(TGF)- β信号稳态平衡的改变与此有关。tgf - β信号参与多种细胞过程。在眼睛中，它起着免疫调节作用，这是眼部免疫特权所必需的。基于对tgf - β信号需要严格调控的假设，我们近年来将研究重点放在鉴定眼内tgf - β信号的内源性拮抗剂和tgf - β信号的下游介质上，这些介质本身可能导致或促成POAG中流出阻力的增加。在初步工作中，我们确定了富含亮氨酸的小蛋白聚糖Decorin （DCN）作为拮抗眼睛中tgf - β信号传导的有希望的候选分子。POAG患者流出组织中的DCN急剧减少，初步数据显示，DCN缺陷小鼠IOP升高，视神经轴突严重丢失。我们的应用是基于这样一个总体假设：DCN是眼睛中一个关键信号系统的一部分，对防止POAG的发生和发展至关重要。本计划的目的是明确DCN在POAG直接影响的眼部组织和细胞，即TM流出通道细胞、视网膜神经节细胞（RGC）和ONH细胞中的功能作用。我们期望获得有关外基质转换的调节机制的相互作用的重要信息，以及TM流出组织和ONH中细胞收缩性的调节。此外，我们期望对RGC体细胞及其轴突稳态所需的机制有更深入的了解，包括星形胶质细胞、小胶质细胞和突触细胞的反应性变化。我们相信，该项目的结果将提供新的信息，具有独特的潜力，导致新的治疗策略，防止POAG的发生和进展。

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.