Retinal Development Research Group
|Michele Madigan||BOptom PhD, Usyd and UNSW|
|Jan Provis||BSc PhD, Prof. Anatomy, Medical School, ANU|
|Nicholas King||Prof. Pathology, USyd|
|Luis Munoz-Erazo||BSc, Postgraduate Student, USyd Pathology and SSI)|
The human ‘macula’ is a specialized area of the primate retina that enables us to see acute detail. Understanding the development and ageing of the macula and how this unique structure makes humans vulnerable to degenerative disease is the principle aim of our research.
The fovea is at the geometric centre of the macula and is identifiable by a number of structural modifications including: (1) an absence of a direct blood supply from the retinal circulation, (2) the presence of a pit which thins the retina locally, (3) a focal concentration of a class of colour sensitive photoreceptors (cones) and (4) the inclusion of specialised circuitry which conserves the electrical responses of individual cones.
Few groups internationally are applying modern molecular tools to the investigation of primate retinal development and human retinal disease. We have developed new approaches to investigate the biology of the macula, our focus being to identify the unique molecular profiles associated with the unique anatomy and physiology of the macula and fovea.
Photoreceptor degeneration in normal ageing and age-related macular degeneration
Madigan, Provis (ANU)
Loss of vision due to AMD is devastating for individuals and families, with very high economic costs to the community. Several lines of evidence indicate photoreceptor dysfunction in early AMD, even when visual acuity is stable, including reduced contrast sensitivity, slowed recovery after photostress, delayed dark adaptation, and reduced amplitude and delayed latency in the foveal electroretinogram (ERG).
Our preliminary work and recent functional studies suggest that visual dysfunction in AMD can occur beyond the central retina, where cone photoreceptors primarily function to give colour vision & fine detail vision. This study investigates photoreceptor survival and degeneration across the human retina in normal ageing & AMD, compared with young normal retinas. Specifically, the early changes in photoreceptors with normal ageing and in AMD are being studied using markers of photoreceptor “wiring” (synapse components), both in central and peripheral regions of the retina. We also address the question of whether degeneration related to normal ageing of photoreceptors is associated with low-level, chronic inflammation in the outer retina.
Most recently we also contributed to an international team that identified the cellular mechanism causing death of retinal pigment epithelial (RPE) cells in dry AMD, in collaboration with Prof Jayakrishna Ambati, and other scientists (Nature 2011: 471(7338) 325-330). In this study, RPE cells in dry AMD are found to downregulate DICER-1 and accumulate Alu, a processor of microRNA, that is upregulated in response to stress. These findings identify a potential target for therapy, but also strengthen the link between metabolic stress, and the progression of AMD. This collaboration is ongoing and aims to identify ways of preventing Alu accumulation, and the agents that trigger stress responses in RPE cells, leading to dry AMD.
The Effect of West Nile Virus Infection on Human Retinal Pigmented Epithelium Extra-cellular Matrix Production
Munoz-Erazo, Madigan, Natoli (ANU), Provis (ANU), King (Pathology, USyd)
AMD is a leading cause of irreversible blindness in the elderly. The pathogenesis of AMD remains elusive. Genetic polymorphisms in the alternative complement pathway (activated by external pathogens) have recently been identified, associated with a strong susceptibility to developing AMD. Numerous studies also indicate a major role for inflammation in the AMD. One hypothesis suggested by these observations is that for individuals with complement-related genetic polymorphisms, exposure to pathogens such as Chlamydia or viruses, may lead to a chronic dysregulated immune response, associated with impaired outer BRB function, leukocyte and blood vessel invasion, and altered extracellular matrix (ECM) production.
We are investigating whether a viral pathogen (West Nile Virus - WNV) can affect RPE production of ECM proteins such as fibronectin, collagen I and IV, and vitronectin These ECM proteins have been associated with cell proliferation, upregulation of angiogenic factors, and several AMD-related diseases such as proliferative retinopathy. Collagen IV and vitronectin are predominant ECM proteins in basal lamina deposits and drusen associated with retinal ageing. Matrix bound VEGF-A will also be measured, as this is a well known angiogenic factor.
Vitreous Development Proteomics
Madigan, Provis (ANU), Sadun (Doheny Eye Institute, USC), Aiello (Joslin Diabetes Centre), Sebag (Doheny Eye Institute, USC)
The vasculature of the embryonic vitreous naturally undergoes regression during development, and this project is using a proteomic approach (vitreomics) to further explore the anti-angiogenic mechanisms involved. To date we have identified 195 membrane-bound and soluble proteins, and found statistically significant changes in 50 of these proteins during the second trimester. These include decreased peroxiredoxin-2, calmodulin and profilin-1, and increased Pigment Epithelium-Derived Factor (PEDF) and cystatin-C. Hyaloid vessel regression appears to be associated with both decreased in pro-angiogenic factors and increased anti-angiogenic proteins. The combined effects of these and other factors may underlie human hyaloid vessel regression and vitreous development. Further studies aim to determine the role of these proteins in regression of the foetal hyaloid vasculature and their potential as novel therapeutics for pathological new vessels growth in the eye.