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Role of Histone deacetylases (HDACs) in retinal degenerations

Inherited forms of retinal degeneration, commonly referred as Retinitis Pigmentosa (RP), result in selective photoreceptor cell death. In most cases, the rod photoreceptors degenerate due to a mutation and the cones die eventually, even though they are not primarily affected. The progressive loss of these cells produces distinctive clinical symptoms: night blindness, constriction of the visual field (tunnel vision), and finally the loss of central vision. The retinal degeneration (rd1, or simply rd) mouse, is one of the most studied RP models and carries a loss-of-function mutation in the gene encoding for the ß-subunit of rod photoreceptor cGMP phosphodiesterase 6 (PDE6). This leads to an accumulation of cGMP, which eventually causes photoreceptor cell death. rd1 retinal degeneration is accompanied by extensive changes in gene expression. Although some of these changes may be the result of direct effects of cGMP on defined genes, it appears likely that the disease also involves more generalized alterations of the transcriptional machinery.

Gene regulation is to a large extent governed by post-translational modifications of histones of which acetylation appears to be one of the most important. Histone acetylation and deacetylation is mediated by histone acetyltranferases (HATs) and histone deacetylases (HDACs), and in general, hyperacetylation may lead to increased transcriptional activity, while hypoacetylation is associated with gene repression.

The focus of my study is the role of HDACs in the rd1 mouse retina, and how epigenetic mechanisms are involved in these inherited diseases. For that we use an ex vivo approach culturing the retina in a physiology mimicking medium and applying different molecules that target different HDAC isoforms. Immunofluorescence, western blotting, and different activity assays are performed to analyze experimental outcomes.

I am about to finish my PhD project under the supervision of Dr. Paquet-Durand and Prof. van Veen in the Department of Experimental Ophthalmology (Centre for Ophthalmology, Tübingen, Germany).

Future "dreams or visions" in vision research

I would like to continue the investigation of the mechanisms implicated in inherited retinal degenerations. But our duty is not only to understand the main molecular mechanisms behind the disease, but also to focus in the discovery of novel targets to stop, or at least slow, the degeneration of the photoreceptors, and maybe, in a future, be able to apply a useful therapy for human patients.

Javier Sancho Pelluz

University of Tübingen
Centre for Ophthalmology
Institute for Ophthalmic Research
Division of Experimental Ophthalmology

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