Current Research

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Foveal Development & Macular Degeneration

Signals from cone photoreceptors provide the basis of almost all of our useful vision. Pathways originating from cones mediate high acuity, colour vision via so-called 'Midget' pathways, which dominate the central few millimeters of primate retina, including the fovea centralis ('fovea'). During early development foveal cones are amongst the first cells to differentiate, appearing as cuboidal, epithelial-like cells. Over the first few years of life they become slender, elongated cells with an elaborate axon, and highly elongated inner and outer segments. A slender shape facilitates close-packing of cones at the fovea, and is the anatomical stubstrate of high resolution vision. In the central fovea, the photoreceptor mosaic comprises cones exclusively, at their highest spatial density; these cones are narrower and more elongated than elsewhere in the retina.

Attainment of adult-like acuity functions in childhood is associated with a slender, elongated cone morphology at the fovea; loss of this morphology is a critical feature of both age-related macular degeneration (AMD) and retinal detachment. Despite the critical relationship between cone shape and visual function, the mechanisms that mediate morphological differentiation during development, and the maintenance of cones through adulthood and old-age, have not been identified. Work in this lab is directed at understanding the mechanisms underlying morphological differentiation of cone photoreceptors, development of the fovea and surrounding macula, and ageing and degeneration of the macula, as occurs in Age-related Macula Degneration.

Retinitis pigmentosa

We are exploring the mechanisms which control the stability of nerve cells of the central nervous system, and whose breakdown results in neuronal death, causing the degenerative disease of the CNS. Many of our projects concern the retina of the eye, and especially the neurones specialised to detect light, the photoreceptors. These highly active and specialised neurones are amongst the most fragile of CNS cells; they degenerate in response to both genetic and environmental stresses. Retinitis pigmentosa (RP) is a diagnosis given to a group of diseases where the insidious death of retinal photoreceptor occurs causes blindness. RP affects 1 person in 4,000, thus about 5,000 Australians and 1-2 million people world-wide. Patients are usually in their late teens or early 20's when diagnosed and they face a life of gathering blindness with no effective treatment. Our laboratory is part of a world-wide effort to find effective treatment

Effects of environmental factors on the rodent retina

Extensive work has been done on the causes of retinal degenerations. About 50% are clearly genetic, the other 50% occur without family history. Several features of retinitis pigmentosa also remain unexplained, particularly the relentless progression of the disease. Many forms of RP are caused by genetic mutation of rod-specific genes, yet the degeneration spreads from the rods to the cones, causing the loss of the entire photoreceptor population and blindness. Recent work in our laboratory led us to formulate an "oxygen toxicity" hypothesis, to explain the progressive nature of the disease. In this series of studies we are looking at the effects of different oxygen levels or light intensity levels on photoreceptor survival in normogenetic and degenerative retinae.   By understanding the mechanisms underlying retinal degenerations, we will be able to model retinal degenerations and to study the effects of therapeutical interventions on these theoretical models, and to use our knowledge in clinical trials.

Protective mechanisms in the rodent retina

Examining the effects of changing environmental factors on the progress of retinal degneration, genetic or environmental, we are learning the process of the disease and the protective mechanisms by which the retina fights to survive. It has become clear in recent years that the degeneration takes place against a background of active resistance by the retina. The mechanisms by which the retina protects itself are also becoming clear. The retina is able to secrete proteins - sometimes called factors - which somehow protect retinal cells against damage. The mechanisms of secretion and action of these factors remain largely unknown. In this series of experiments we assess the role of protective (neurotrophic) factors in the normal retina's resistance to stress, such as light damage, identify the high-affinity receptors involved and trace their regulation by genetic and environmental stress. By using electroretinography we also assess the direct effects of these factors on photoreceptor function.

Molecular Mechanisms of Retinal Generation

In this project gene arrays are used to survey the range of gene expression occuring during stress. Initial surveys identify major classes of genes up- or down-regulated in oxygen stress and during the progress of retinal degeneration . More detailed studies and analysis of interesting genes, their mRNA and protein expression and regulation, will follow.

Roles of Mitochondria in Retinal Degenerations

Mitochondria serve (at least) 3 functions in every cell. They are the site of oxidative metabolism, and the source of signals which induce or suppress apoptotic (programmed) cell death. Mitochondria are abundant in photoreceptors, and we have begun testing whether mitochondrial damage is a factor in photoreceptor degeneration. We have shown for the first time that deletions in mtDNA (mitochondrial DNA) are abnormally frequent in degenerating retina. Recent studies have shown that somatically aquired mutations such as deletion of mtDNA are caused by oxygen damage or UV irradiation during the life of the individual. Accumulation of these somatic mutations in postmitotic cells (such as neurones) causes bioenergetic deficiency leading to age-associated dysfunction of cells and organs. An accelerated accumulation of mtDNA fragmentation leads to premature ageing and/or degenerative diseases. In this study we are screening photoreceptors of normal ageing and degenerative retinae . We are also looking at the role of mtDNA deletions in light induced retinal degenerations.

Visual System Development

Development of the visual system using the marsupial mammal, the wallaby, as a model. The protracted and largely postnatal development of the visual system in the wallaby, combined with features it shares with higher placental mammals, make it an excellent alternative model for developmental studies. It permits unrivalled access for experimental manipulation at early stages.  Molecular mechanisms involved in the establishment of cortical areas and their connections and in the establishment of the topographic map made by retinal axons in the midbrain are being investigated. Molecules being examined include brain-derived neurotrophic factor and Ten_m3, a transmembrane protein. A stereotaxic atlas of the wallaby brain is available here.

 Motor Disorder

In general, research interests lie in the neural pathways and circuits that generate movement, those that make things happen. The inability to control ones movement and/or posture is a terrifying and striking affliction. Perhaps the best known movement disorder is Parkinson disease where individuals suffer a variety of symptoms including tremor (shaking), slowness of movement and stiffness (statues). Parkinson disease manifests after a loss or degeneration - by causes unknown - of several cell groups or centres in the brain, particularly in the basal ganglia, thalamus and brainstem. These losses contribute substantially to creating the shaking (tremors) and statues (stiffness) seen in individuals with the disease. In this lab, we explore the circuits and pathways involved in normal movement and examine the suspected abnormal mechanisms that may manifest in the shaking and/or the statues. We are also looking at mechanisms that generate the loss of cells in the disease, together with ways in which to save the cells from death. We use modern anatomical methods, such as tract-tracing and immunocytochemistry to examine these issues.

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