Research
Projects - Theme 3
Theme 3: Vision for Life: The challenge of degenerative disease
Theme Leader: J. Stone
- Oxygen-induced gene expression in the adult retina
- The impact of hyperoxia on the electroretinogram in the rat and human retina
- Oxygen metabolism in the healthy and degenerating retina
- Retinal patterning: Siting the fovea and the rod-free area
- Indicators of retinal stress and photoreceptor degeneration in AMD retinas and fellow-eyes
- Testing the hypothesis that morphological differentiation of cones is mediated by FGF signalling in a primate model, the marmoset
- Looking for the Building blocks that make the fovea function
- In vivo effects of near-infrared light on the healthy mammalian retina
- Effects of near-infrared light exposure on the degenerative, unstable retina
- The role of mitochondria in retinal degeneration
- Modelling retinal degenerations: Lessons from the RCS rat
- Control of eye growth: Optically generated signals and molecular pathways
Oxygen-induced gene expression in the adult retina (Stone, Valter)
This study will use microarray and real-time PCR techniques to demonstrate changes in gene expression induced by exposure of the retina to hyperoxia (high levels of oxygen). The issue is of interest because high tissue oxygen levels are a reliable feature of the adult stages of all retinal degenerations, and the toxicity of the oxygen appears to be a factor in the progression of the disease. These studies will be done on rodent (rat, mice) models of retinal degenerations. Our preliminary data show a biphasic effect of hyperoxia, which regulates different genes at short and long intervals after the onset of hyperoxia. These data will provide a basis for understanding the cell biology of the aging and degenerating retina, and for devising techniques to slow and prevent the degeneration of photoreceptors, and the consequent blindness.
The impact of hyperoxia on the electroretinogram in the rat and human retina (Stone, Valter, Lamb)
This study will explore the impact of hyperoxia on the function of photoreceptor, assessed by the a-wave of the dark-adapted electroretinogram (ERG). These results will be compared with those for gene expression. Again, preliminary data indicate a biphasic effect; hyperoxia initially enhances and then degrades the ERG. This work will also be done on a range of rodent models of retinal degeneration. These data will provide a basis for the use of hyperoxia to provide temporary enhancement of retinal performance, and for reducing hyperoxia over the long term, to improve the long term stability of the retina.
Oxygen metabolism in the healthy and degenerating retina (Yu, Cringle)
Our studies will use oxygen sensitive microelectrode technology to make measurements of oxygen tension across the living retina and to analyse such data to quantify the rate of oxygen uptake in specific retinal layers. The results will lead to an increased understanding of oxidative stress in the degenerating retina, oxygen metabolism of the macula, and regeneration of function and sensitivity in previously stressed photoreceptors.
Retinal patterning: Siting the fovea and the rod-free area (Provis, Bumsted O'Brien)
This study aims to identify genes and proteins associated with the positioning of, and specialization in, the macula and fovea region by comparative analysis with developing avian optic cup and in situ analysis of gene expression in developing human retina.
Indicators of retinal stress and photoreceptor degeneration in AMD retinas and fellow-eyes (Provis, Maddess)
This study will explore further the cell biology and cone function in normal adult human retinas and in the fellow eyes of AMD retinas. We will identify early morphological and molecular changes that herald the development of AMD, with a long term view to developing intervention strategies.
Effects of stress and degeneration on cone morphology and immunoreactivity in rat and ageing human retina. (Provis, Valter, Bumsted O'Brien)
Our recent analysis of aged human retinas found that cone photoreceptors appear more vulnerable to stress-related changes than rod photoreceptors; rods, however, appear to succumb to the effects of stress and die before cones. In this study we aim to carry out comparative studies using adult rat retinas subjected to a variety of stressors, and ageing rats, to identify features of the cone response to stress that resemble human cones in ageing, to help us to model cone degeneration associated with ageing.
Looking for the Building blocks that make the fovea function (Bumsted O'Brien, Provis, Ibbotson)
It is generally agreed that the function of a fovea is to enhance visual acuity, although there is some confusion over how this is achieved. Are all foveae functionally the same- that is does the presence of a fovea provide a visual advantage? We are addressing this using two seahorse species; one with foveal pit ( H. abdominalis ) and one lacking a foveal pit ( H. kuda ) to determine whether the presence of a fovea provides higher visual acuity. Assuming the function of a fovea in the retina is to enhance visual acuity, what is the significance of the different foveal morphologies? Our experiments will use the foveate pigeon and seahorse retina to test whether foveae morphological forms reflect differences in the relative proportions, distribution and functional interplay between M-(like) and P-(like) circuits.
In vivo effects of near-infrared light on the healthy mammalian retina (Valter, Stone)
It has been demonstrated that exposure to near-infrared light (NIRL) facilitates wound healing in muscles, mucosal tissue and the peripheral nervous system. This project will explore the effects of NIRL radiation on the mammalian retina in vivo .
Effects of near-infrared light exposure on the degenerative, unstable retina (Valter)
Retinitis pigmentosa is a degenerative disease of the retina, which affects around 1 million people world-wide. This disease leads to a loss of vision. The loss of vision is usually attributed to the loss of photoreceptors. Our laboratory has shown that part of the blindness of sufferers is due to a loss of visual function of the surviving photoreceptors. In this project, we investigate how the environment of the retina (light, oxygen, mitochondrial status) affects the function of photoreceptors.
The role of mitochondria in retinal degeneration (Valter)
This study will identify damage to mitochondrial DNA in the cascade of events leading to apoptosis of photoreceptors by using real-time PCR, bio-analysis and gene array techniques. This will help understanding the mechanism/s leading to photoreceptor death during retinal degeneration, and more importantly, to see the differences in the mechanism leading to cell death in the face of different stress (light versus oxygen; genetic vs. environmental; genetic versus genetic). If during the investigation we find some common trends, we could target those when planning protective actions.
Modelling retinal degenerations: Lessons from the RCS rat (Valter, Yu, Cringle)
The photoreceptor dystrophy of the Royal College of Surgeons (RCS) rat is known to be driven by a single autosomal recessive mutation which affects the phagocytotic function of the retinal pigment epithelium. We will explore the possibility that hypoxia in the early stage of dystrophy in the RCS rat is the result of a retinal detachment caused by debris formation, while the later stages of degeneration are due to hyperoxic toxicity. Creating a comprehensive model of this degeneration will allow us to test therapeutic measures, as well as provide a firm foundation for modelling other retinal degenerations.
Control of eye growth: Optically generated signals and molecular pathways (Morgan)
Regions to Australia's north, in urban East Asia, are currently afflicted with an epidemic of myopia, where as much as 80-90% of the young adult population will have high life-long high costs of optical correction, and as much as 20% of that population is at high risk of later blindness. This study aims to characterise the retinal, choroidal and scleral pathways that control eye growth (myopia is simply an eye that has grown too long). There is a particular focus on the control of eye growth, dopamine release, and candidate gene expression, by light and optical defocus. These approaches, in combination with externally funded epidemiological studies, have led to two potential interventions for the control of myopia – imposed myopic defocus for short periods every day, and increasing the amount of time children spend outside in bright outdoor light. These interventions are now being trialled in Singapore and Guangzhou .
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