Neurodegeneration in the Retina: Effect of the Glial Pigment Epithelium-Derived Factor (PEDF)

• Applicant: Professor Dr. Andreas Reichenbach
• Subject Area: Ophthalmology
• Term: from 2008 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 92219473

The retina of diabetic patients undergoes chronic degenerative changes in both the vascular and the neuronal system, which may ultimately lead to irreversible loss of vision. This project places emphasis on the regulation and effects of pigment epithelium-derived factor (PEDF), which mainly occurs in the retina due to its production by retinal glial (Müller) cells. PEDF plays important roles as an anti-angiogenic as well as a neurotrophic/ -protective factor. Given these activities, PEDF is an appropriate candidate molecule to prevent both neovascularization and neuronal degeneration in the retina. To improve our understanding of these particular PEDF-inherent functions, transgenic animals are to be generated which allow to manipulate Müller-cell derived PEDF expression towards an overexpression. In the course of hitherto performed work we have developed appropriate constructs required to accomplish this goal. We anticipate that the proposed experiments involving these animals will shed light on how survival of metabolic stress-exposed neurons (and endothelial cells) is modulated by glial PEDF production. We have generated in vitro data indicating an increased PEDF release from Müller cells under hypoxia, with a PEDF upregulation that was controlled by HIF-1 und VEGF. PEDF was shown by us to support retinal ganglion cell survival (which was markedly attenuated under hypoxia); furthermore, its activity inhibited the hypoxia-induced VEGF production by Müller cells. Finally, our studies identified a new binding molecule as a putative PEDF receptor on retinal microvascular endothelial cells which suggests that PEDF may interfere with PlGF and VEGF binding to these cells, providing a new explanation for its anti-angiogenic activity. Here we propose to investigate by further work in our project whether transient hypoxia, followed by re-oxygenation, causes an increase of Müller-cell derived PEDF production. Finally, further experimental work will be aimed at elucidating whether the novel PEDF binding molecule identified by us, is involved in signaling mechanisms occurring in stimulated retinal endothelial cells.

• DFG Programme: Research Grants
• Participating Persons: Dr. Petra G. Hirrlinger; Professor Dr. Peter Wiedemann