At present, the only treatment for glaucoma is intraocular pressure control. We know some people still get worse despite good pressure control. We have evidence that a system previously only thought to modulate blood pressure control has an important role in halting glaucoma damage. We would like to examine this system further in a glaucoma model further as well as examine a known relationship with another protective growth factor. Using molecular biological techniques we aim to see how raised intraocular pressure affects these systems so we know which parts of the pathway may be best to target for potential treatments for glaucoma in the future.
The renin-angiotensin system (RAS) is distributed ubiquitously in the rodent eye. We have data demonstrating that modulation of angiotensin II receptors in an ex vivo rodent model confers neuroprotection likely through modulation of superoxide (free radical) formation. These findings are in keeping with findings from other researchers that have demonstrated that excess superoxide generation plays a critical role in intracellular cell signalling on the path to retinal ganglion cell apoptosis in addition to its innate toxicity. In addition, the neuroprotective role of angiotensin blockade in neuroprotection including modulation of superoxide generation has been demonstrated in ocular hypertension models of glaucoma in vivo.
However, systemic administration of Angiotensin II blockade is problematic as impaired intraocular perfusion may be a mechanism of glaucoma progression; particularly in normal tension glaucoma. The active form of angiotensin II blockers are also very water insoluble meaning non-invasive localised therapy may be problematic. However, downstream from AT1R and AT2R, the Angiotensin II receptors in the eye, is a neuropeptide based system that acts at the receptor MAS in an antagonistic fashion to AT1R. It has only very recently been described in the cardiovascular literature and is dependent on the enzyme ACE2. This system can be modulated in the eye by water soluble agents already FDA approved.
The aim of this project is to characterise this new ACE2 dependent downstream pathway in the eye which has never been described fully here before and look for targets that can be modulated to confer neuroprotection suitable for clinical trial.
We aim to generate glaucoma in rats using established techniques and examine how components of this system change with glaucoma utilising histological and immunofluorescence techniques as well as Real Time PCR. The next step would be to try to prevent these changes using candidate drugs. This project involves collaboration with colleagues at Macquarie University, University of NSW, Flinders University and the University of Cambridge.
The opportunity ID for this research opportunity is 1828