As part of the Macular Research Group, we investigate the contribution of the outer retinal metabolism to retinal health. Our research has a particular focus on Müller cell dysfunction and manipulation.
Our laboratory research seeks to understand some of the key unresolved issues in ophthalmic research and health. These include:
By tackling these questions, we hope to come closer to understanding and treating macular diseases such as age-related macular degeneration, diabetic macular edema and macular telangiectasia.
Photoreceptor degeneration is a major feature of macular diseases such as age-related macular degeneration, diabetic macular edema and macular telangiectasia.
It's likely that issues with the metabolism of glucose in the retina is a factor in photoreceptor degeneration. We know that:
However, how metabolic dysfunction affects photoreceptor health remains largely unknown – an issue that our research is seeking to understand.
Another major unresolved issue in vision research is why the central retina, or macula, is particularly susceptible to some of the commonest blinding diseases, such as age-related macular degeneration and diabetic macular oedema. We hope to provide insights into this question.
We currently have three streams of laboratory projects, each addressing a different area of macular health with a focus on Müller cells.
We have generated a unique transgenic mouse in which a Müller cell-specific promoter along with the Cre/Lox-P approach was used for Müller cell-specific gene targeting.
We also have transgenic lines carrying cell-specific promoters which allow us to manipulate gene expression in photoreceptors and the retinal pigment epithelium (RPE).
We are currently using these unique cell-specific approaches to study the consequences of selectively disrupting various metabolic pathways in Müller cells, rod photoreceptors and the RPE in the intact retina. This will allow us to precisely dissect the contribution of metabolic derangement in Müller cells, photoreceptors and the RPE to photoreceptor degeneration in retinal diseases.
We have generated an inducible transgenic line which allows us to specifically manipulate gene expression in Müller cells (Figure 1A). We have crossed this transgenic line with transgenic mice carrying an attenuated form of the diphtheria toxin gene and found that selective Müller cell ablation leads to photoreceptor degeneration, retinal vessel leak, and later, intraretinal neovascularisation (Figure 1B-H).
These changes are also accompanied by reactive activation of retinal glia including astrocytes, surviving Müller cells and microglia.
These features make our transgenic mice very useful for studying the cellular and molecular mechanisms underlying Müller glia-neuron-vascular interactions.
Our transgenic mice can also be used to test novel strategies for neuroprotection, inhibition of retinal vessel leak and prevention of retinal fibrosis.
We believe that one of the important differences between the macula and the rest of the retina is the nature of the Müller cells, the retina’s main glial cell, in the 2 regions.
We have found significant differences between Müller cells from the macula and peripheral retina at the transcriptional level. Of note are differences in the de novo serine synthesis pathway, which controls cell susceptibility to stress.
We believe Müller cells derived from the central and peripheral retina have different susceptibility to stress due to the differences in this pathway. We aim to compare de novo serine synthesis in central and peripheral Müller cells as well as to understand the pathological consequences of disturbing this pathway in Müller cells.
We will further test compounds that can compensate for derangement of Müller cell de novo serine synthesis.
This will be the first study to compare Müller cells from human macula and peripheral retina as well as to investigate the role of de novo serine synthesis in Müller cells in health and disease.
The significance of this research is that it may provide insights into a major unresolved question in vision research: why is the macula so susceptible to some of the commonest blinding diseases such as age-related macular degeneration and diabetic macular oedema.