The role of Dystrophin 71 in Müller cells and vasoproliferative retinal disease

• Applicant: Dr. Felicitas Bucher
• Subject Area: Ophthalmology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262548836

Vasoproliferative retinopathies are important causes of visual impairment in the developed world. Abnormal endothelial cell sprouting causes aberrant blood vessel growth. Changes in endothelial cell physiology is not the only reason for pathologic vascularization. Neuronal and glial cells have been shown to play an important role in maintaining and directing retinal blood vessels. However, molecular mechanisms in the glial-endothelial-interaction are not yet completely understood. Clinical observations and retinal morphology suggest that Müller cells participate in retinal angiogenesis. Müller cells possess perivascular endfeet at the inner retina that participate in the formation of the blood-retinal barrier. Müller cells are also believed to play an important role in the development of the deep vascular plexus.Clinical observations have shown that patients suffering from muscular dystrophies due to defects in dystrophin expression are prone to develop proliferative retinopathies in late stages of respiratory insufficiency. Further studies discovered that Dystrophin 71(Dp71) accumulates in perivascular Müller cell endfeet. Preliminary data suggest that in the mouse model of oxygen-induced retinopathy (OIR model) retinal neovascularization is increased in Dp71-deficient mice compared to littermate controls.This project aims to further investigate the role of Dp71 in Müller cells and vasoproliferative disease. The retinal phenotype of Dp71-deficient mice in the OIR model will be further characterized in respect of retinal neovascularization, vascular leakage and retina function. Viral vectors potent to selectively transduce retinal Müller cells with intact Dp71 will be used to treat Dp71 deficient mice and rescue the retinal phenotype. In vitro assays will complement our understanding about molecular pathways of Dp71. We will investigate the impact of Dp71 on retinal expression levels of soluble proangiogenic mediators like the Vascular Endothelial Growth Factor. Moreover, Dp71 has been shown to be an important component of a transmembrane protein complex at the perivascular Müller cell endfeet. Therefore, we will evaluate the direct cell-cell interaction between Müller cells and endothelial cells.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Martin Friedlander