The Functional Role of Decorin in Glaucoma

• Applicant: Professor Dr. Rudolf Fuchshofer
• Subject Area: Ophthalmology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 357014458

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.

• DFG Programme: Research Grants