Molecular mechanisms of photoreceptor protection in rat models of degenerative retinal disease

Project Aim

The aim of this project was to gain a deeper understanding of the biology of the retina in the context of degenerative retinal disease. Specifically, this project investigated how the retina is able to protect itself by expressing trophic factors (homeostatic signalling molecules). We also observed how vision loss as a result of retinal degeneration is caused from the death of retinal cells, but also from damage to surviving cells, and how this opens up the possibility of partially restoring vision in patients living with degenerative retinal disease.

Project Summary and Impact

We Investigated the effect of trophic factors on the retina. These are factors expressed by cells in the retina which have a protective effect. We looked at which cells express these factors, where they act, and the impact these factors have on the function of retinal cells. It was found that not only do these trophic factors have a protective effect on retinal cells, but they also suppress the cells responsiveness to light.
We also investigated the early involvement of metabolic mechanisms in the death of photoreceptors (the cells in the retina responsible for detecting light). Perhaps the most important finding from this project was evidence that vision loss in the context of retinal degeneration was only partly caused by the death of retinal cells (which is irreversible), but also from damage to the surviving retinal cells (which may be reversible). Furthermore, simply by managing the overall light exposure the rats received, evidence showed that their visual performance could be improved. We are currently extending our work to investigate other ways of restoring visual function to the retina, including by the manipulation of light and by a new approach utilising near infrared radiation.
These findings were reported to Retina Australia in 2004 and the results of this project were published across ten scientific papers and reviews, and has become the basis for several projects currently underway.

For years it has been assumed that vision loss in degenerative retinal conditions such as Retinitis Pigmentosa is caused entirely by the death of retinal photoreceptors and is therefore irreversible without major invasive intervention (e.g. transplantation). Our work opens up the possibility of partially restoring vision loss in patients living with a degenerative retinal disease by managing the retina’s exposure to light, oxygen and other potential techniques such as infrared radiation.

Published Peer Reviewed Articles

Valter K, Bisti S, Gargini C, Di Loreto S, Maccarone R, Cervetto L, Stone J. Timecourse Of Neurotrophic Factor Upregulation Following Unilateral Optic Nerve Section. Investigative Ophthalmology and Visual Science. 2005, Vol 46: 1748 – 1754.

Stone I, Sandercoe TM, Provis J. Mechanisms of the Formation and Stability of Retinal Blood Vessels. Ocular Angiogenesis, 2006: 101-106.

Yu DY, Cringle S, Valter K, Walsh N, Lee D, Stone J. Photoreceptor death, trophic factor expression, retinal oxygen status, and photoreceptor function in the P23H rat. Invest Ophthalmol Vis Sci. 2004, 45: 2013-2019.

Walsh N, Van Driel D, Lee D, Stone J. Multiple vulnerability of photoreceptors to mesopic ambient light in the P23H transgenic rat. Brain Res. 2004, l013: 194-203.

Stone I, Mervin K, Walsh N, Valter K, Provis I, Penfold P. Photoreceptor stability and degeneration in mammalian retina: lessons from the edge. In: Penfold P, Provis J, eds. Macular Degeneration: Science and Medicine in Practice. Springer Verlag; 2004; 149-165.

Gargini C, Bisti S, Demontis G, Valter K, Stone J, Cervetto L. ERG changes associated with retinal upregulation of trophic factors: observations following optic nerve section. Neuroscience. 2004; 126: 775-783.

Bravo-Nuevo A, Walsh N, Stone J. Photoreceptor degeneration and loss of retinal function in the C57BL/6-C(2J) mouse. In»est Ophthalmol Vis Sci. 2004; 45: 2005-12.

Geller SF, Stone J. Quantitative PCR analysis of FosB mRNA expression after short duration oxygen and light stress. Adv Exp MedBiol. 2003; 533: 249-57.

Bravo-Nuevo A, Williams N, Geller S, Stone J. Mitochondrial deletions in normal and degenerating rat retina. Adv Exp MedBiol. 2003; 533: 241-8.

Valter K, Driel DV, Bisti S, Stone JS. FGFRI Expression and FGFRl-FGF-2 Colocalisation in Rat Retina: Sites of FGF-2 on Rat Photoreceptors. Growth Factors. 2002; 20: 177-188.

Download the Researcher's Final Report

Chief investigator:
Professor Jonathan Stone
University of Sydney

Co-investigator/s:

Dr Kristina Valter, Australian National University, Canberra

Grant awarded:
$30,000 (2002), $30,000 (2003)