Lead Researcher: Professor Gregory Dusting
Research into Cytoprotection Pharmacology explores cellular signalling that regulates cell survival, proliferation (where cells divide and multiply) and differentiation (where a cell develops into a more specialised cell). Angiogenesis (growth of new blood vessels) is a particular focus, both for exploring its potential in tissue regeneration, and treating diseases in the retina. By understanding the underlying mechanisms, we aim to develop new approaches for the treatment of vision threatening diseases such as age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and ocular tumours, all of which result at least partly from pathological neovascularisation (excessive blood vessel growth).
- Developing potential new drugs to inhibit angiogenesis and treat vision loss
- Endothelial cell function and regulation of the vessels in the retina
- Biochemical signalling using pharmacological intervention and endothelial progenitor cells
- Exploring the involvement of redox signalling in differentiation of adult mesenchymal stem cells and induced-pluripotent stem cells into cardiac and ocular cell lineage
Developing potential new drugs to inhibit angiogenesis and treat vision loss
Many diseases that cause major loss of vision do so as a result of pathological neovascularisation. Effective and inexpensive treatments for targeting ocular neovascularisation are a priority in ophthalmology. We are investigating the therapeutic potential of new drugs to inhibit angiogenesis, which can be delivered long term and using a non-invasive method. This will help avoid the current need for repeated, painful injections into the eye.
Endothelial cell function and regulation of vessels in the retina
Maintaining retinal blood vessel function is crucial for healthy vision. Changes to retinal circulation have been linked to eye diseases such as diabetic retinopathy, macular degeneration and glaucoma. Whilst retinal blood flow changes can be easily assessed, the self-regulation of blood vessels, in particular the function of the cells that line the inside of blood vessels – the vascular endothelial cells – is not well understood.
We are developing a way to assess endothelial cell function in the eye in rats. Chemical agents will be delivered via a thin tube inserted near the retinal vessels to see how the vessels react in normal and diabetic rats. Dynamic imaging and electrophysiology (measuring the electrical activity of a cell or tissue) will be used to assess function in the retina, using new facilities at the Melbourne Brain Centre.
This will be a useful tool for testing the effects of potential agents on restoring vascular function in eye diseases.
Biochemical signalling using pharmacological intervention and endothelial progenitor cells
Neovascularisation is involved in the repair of tissues such as heart and retina after they have been starved of oxygen. This is an indispensable process for tissue repair which involves proliferation, migration and capillary formation from endothelial and progenitor cells. A progenitor cell is similar to a stem cell because it can become a more specialized cell down the track. However, progenitor cells have a limited number of cells which they can become, unlike stem cells which can become any type of cell in the body.
Redox signalling is a process whereby molecules (including reactive oxgen species – ROS) lose or gain electrons while acting as chemical messengers. Redox signaling is essential for a number of biological processes, including energy production and protecting against the harmful effects of free radicals.
Research has found that redox signalling has a role in angiogenesis in vivo (in a living organisim) in the heart and retina. However, we don’t know exactly how ROS contribute to signalling in the developing vessel architecture and what their involvement is in vessel function.
We have discovered drug molecules that specifically induce the expression of a particular ROS called NADPH oxidase 4 (Nox4) in endothelial cells and progenitor cells. We will investigate the role of Nox4 in endothelial progenitor cells both in vitro (in a test tube) and in vivo, and their involvement in neovascularisation, which is important for repairing organs such as heart and retina after injury.
Is redox signaling a new key to differentiation of stem cells into eye cells?
Excessive production of reactive oxygen species (ROS) induces oxidative stress in cells. This may lead to modification of lipids, proteins, and DNA, damaging the cell structure. However, it is becoming clear that lower levels of ROS within the cell may be involved in regulating fundamental cell behaviours, such as differentiation. Understanding the redox mechanisms that mediate adult and induced-pluripotent stem cell proliferation and differentiation will be of great value in developing new strategies to produce various cardiac and ocular cells of several types, which will be of benefit for direct transplantation, or tissue engineering of cardiac and eye tissues.