The importance of protein kinase G (PKG) for cGMP-dependent cell death and neuroprotection in inherited retinal neurodegeneration

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Retinitis Pigmentosa (RP) is a group of inherited retinal degenerations which constitutes one of the leading causes of blindness in the developed world. These are at present untreatable and the underlying neurodegenerative mechanisms are unknown even though the genetic causes are often established. Since elevated levels of cyclic guanosine monophosphate (cGMP) are responsible for photoreceptor cell death in different animal models for human RP, differential regulation of factors involved in cGMP signalling may represent a novel approach for the treatment of RP. The aim of this study is to investigate cGMP-signalling and its role in photoreceptor degeneration using in vivo, ex vivo, and in vitro techniques. The project will focus on the activity of cGMPdependent protein kinase G (PKG), its potential targets during retinal degeneration, and the identification of neuroprotective strategies to halt or delay processes leading to blindness. This will be accomplished by in vivo phenotyping of treated and untreated mice of the lines studied, and the follow-up of degenerative events in the same individual animals using state-of-the-art, non invasive technology for both functional and morphological characterization. At certain time points, a number of animals will be sacrificed for ex vivo studies with emphasis on assessing metabolic activity of calpains, poly-ADP-ribose-polymerase (PARP), and histone deacetylases (HDAC) as potential downstream effectors of cGMP-PKG. New data on processes active during retinal neurodegeneration will serve as basis for developing and testing novel experimental treatments on in vitro retinal explants, and where applicable, in vivo.