The aim of this project is to better understand the events that cause the onset of uveitis, a common cause of visual impairment and blindness in adults. Toll like receptors (TLR) are a new group of cell surface receptors tinflammatory mediators.hat are important in immune function and the immune system's ability to recognise and respond to to microbes by recognising signature molecules contained in microbes. The TLR system is the early warning system of immune defence and activation of the TLR s ....The aim of this project is to better understand the events that cause the onset of uveitis, a common cause of visual impairment and blindness in adults. Toll like receptors (TLR) are a new group of cell surface receptors tinflammatory mediators.hat are important in immune function and the immune system's ability to recognise and respond to to microbes by recognising signature molecules contained in microbes. The TLR system is the early warning system of immune defence and activation of the TLR system induces the generation of multiple mediators that initiate and perpetuate inflammation. There has been intense interest and research into this novel family of receptors and they have been shown to play an important role in human diseases such as inflammatory bowel disease and psoriasis. The role of TLRs in uveitis has not been studied. We hypothesise that TLRs play a central role linking certain bacteria and the induction of uveitis. TLR4, a member of the TLR family has been clearly identified as the key receptor for cell wall components of gram negative bacteria (a chemical called LPS). In vitro data shows that TLR4 stimulation by LPS causes the release of inflammatory mediators. This project is designed to study the expression of TLRs in the eye, factors that control their expression and the results of stimultaing TLRs with their target chemicals. Better understanding ofd the causes and mechanisms of uveitis will allow the development of more specific and effective treatments.Read moreRead less
DISSECTING THE GENETICS OF GLAUCOMA AND ITS RISK FACTORS USING A TWIN STUDY.
Funder
National Health and Medical Research Council
Funding Amount
$682,850.00
Summary
Glaucoma is one of the leading causes of blindness both in Australia (affecting 2-3% of the population) and worldwide. Glaucoma is often asymptomatic until it causes permanent loss of peripheral vision that precludes 10% of individuals with the condition from holding a driver's license. Around 50% of people with glaucoma are unaware that they have the condition; therefore better screening strategies are required. Genetic factors have been shown to contribute to glaucoma and our work has revealed ....Glaucoma is one of the leading causes of blindness both in Australia (affecting 2-3% of the population) and worldwide. Glaucoma is often asymptomatic until it causes permanent loss of peripheral vision that precludes 10% of individuals with the condition from holding a driver's license. Around 50% of people with glaucoma are unaware that they have the condition; therefore better screening strategies are required. Genetic factors have been shown to contribute to glaucoma and our work has revealed that 50% of people with glaucoma have a family history of the condition. Raised intraocular pressure (IOP) is a major contributing factor in glaucoma. Although there are some genes associated with high-pressure glaucoma, little is known about the heritability of IOP itself. Optic disc cupping is another important sign in the diagnosis and management of glaucoma, but again little is known of the inheritance of this feature. Twin studies, (comparing sets of identical twins with non-identical twins); allow us to estimate the relative contribution of genetic and environmental factors to disease states or physiological measurements. Although there have been small studies involving twins with glaucoma, it is unknown to what degree the basic parameters of glaucoma diagnosis such as IOP and optic disc characteristics are heritable. This project aims to conduct a large twin study into glaucoma and its associated ocular risk factors, including refractive error. We aim to identify genes that predispose to glaucoma, which will facilitate better screening for glaucoma in family members, and the general population, and ultimately leading to improved treatment.Read moreRead less
A Multicentre Randomised Clinical Trial Of Laser Treatment Plus Intravitreal Traimcilone For Diabetic Macular Oedema
Funder
National Health and Medical Research Council
Funding Amount
$529,500.00
Summary
A diagnosis of diabetes immediately confers a 25 fold increase in a person's risk of blindness. The macula is the vision centre of the retina, which is like the film in a camera. In people with diabetes, swelling of the macula (macular oedema) due to leakage of retinal blood vessels is the commonest cause of loss of vision. Laser treatment is proven to be helpful in reducing the risk of vision loss in eyes with diabetic macular oedema (DMO), but it does not work in 40% of cases. Injection of slo ....A diagnosis of diabetes immediately confers a 25 fold increase in a person's risk of blindness. The macula is the vision centre of the retina, which is like the film in a camera. In people with diabetes, swelling of the macula (macular oedema) due to leakage of retinal blood vessels is the commonest cause of loss of vision. Laser treatment is proven to be helpful in reducing the risk of vision loss in eyes with diabetic macular oedema (DMO), but it does not work in 40% of cases. Injection of slow release steroids is an emerging revolutionary treatment for DMO. We are the first in the world to perform a randomised clinical trial of triamcinolone injection into the eye with DMO that has failed laser treatment. A randomised clinical trial is when an equal number of eyes are randomly allocated to the treatment and placebo (no treatment) groups, so that none of the patients or the doctors knows whether each particular eye is receiving treatment or placebo. The preliminary results of our study in progress have proved that, at least in the short term, intravitreal triamcinolone (IVTA) leads to reduction of macular oedema and improved vision. We now propose a two year randomised clinical trial to test whether the combination of IVTA with laser treatment will result in a further improvement in vision in eyes with DMO. We are in a unique position to conduct such a study, having recently concluded the world's first randomised clinical trial of IVTA for wet age-related macular degeneration in 151 eyes. We have extensive experience of IVTA's significant but manageable adverse event profile. The Australian Retinal Collaboration is a group of academic retinal specialists who are committed to attaining the highest possible standards in clinical research in Australia for common blinding conditions of the retina. The results of the proposed study are likely to lead directly to a reduction of the risk of vision impairment and blindness in people with diabetes.Read moreRead less
Characterising The Changes In Regulation Of Visual Contrast Sensitivity In Glaucoma.
Funder
National Health and Medical Research Council
Funding Amount
$337,600.00
Summary
Glaucoma is the second leading cause of blindness in developed nations. A recent study estimated the number of Australian's that will need regular visual examination in 2030 either because they have glaucoma or glaucomatous risk factors to be at least 800,000. As the ultimate aim of glaucoma treatment is to maintain vision, visual functional assessment is of paramount importance to glaucoma management . The current standard measure for the assessment of visual loss due to glaucoma is visual fiel ....Glaucoma is the second leading cause of blindness in developed nations. A recent study estimated the number of Australian's that will need regular visual examination in 2030 either because they have glaucoma or glaucomatous risk factors to be at least 800,000. As the ultimate aim of glaucoma treatment is to maintain vision, visual functional assessment is of paramount importance to glaucoma management . The current standard measure for the assessment of visual loss due to glaucoma is visual field testing. Regrettably, substantial damage to retinal ganglion cells (the primary neurons affected by glaucoma) is often present prior to the discovery of visual field loss using standard measures. Indeed studies have demonstrated that even 30-50% retinal ganglion cell loss may only manifest as a mild visual field deficit using current standard testing. This project will use novel techniques for exploring sight impairment in glaucoma, enabling a better understanding of the underlying neural damage. Our pilot work demonstrates that these methods can detect loss of sight in areas diagnosed as normal using standard visual field testing. The study will provide new technologies for the assessment of early vision loss due to glaucoma that may enable the detection of malfunction of retinal ganglion cells prior to their death. Such measures of neural malfunction are essential to establishing the efficacy of new pharmacological therapies (known as neuroprotective agents) for glaucoma aimed at keeping retinal ganglion cells alive and functioning. This project also has the potential to identify visual measures that have better capability for monitoring the progression of vision loss due to glaucoma. Early detection of glaucoma and its progression is essential so that treatment can be initiated or altered, slowing the progression of vision loss and its toll on both the individual and the community.Read moreRead less
Regional Immunosuppression For Corneal Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$268,264.00
Summary
Blindness exerts major physical, emotional and economic constraints and hardship upon the sufferer. Corneal transplantation is a well-accepted surgical treatment for visual impairment caused by opacification of the cornea, the transparent window at the front of the eye. Corneas for transplantation are retrieved from people who have recently died, after permission has been sought from the donor's family. Unfortunately, a significant proportion of corneal transplants fail because they are recogniz ....Blindness exerts major physical, emotional and economic constraints and hardship upon the sufferer. Corneal transplantation is a well-accepted surgical treatment for visual impairment caused by opacification of the cornea, the transparent window at the front of the eye. Corneas for transplantation are retrieved from people who have recently died, after permission has been sought from the donor's family. Unfortunately, a significant proportion of corneal transplants fail because they are recognized as foreign, and undergo rejection by the recipient. Once a corneal graft has failed, it is no longer transparent to light. A number of novel interventions are being developed to reduce the incidence of corneal graft rejection, but at present it is uncertain exactly how these should be delivered to the patient. The research described in this application is designed to discover how therapeutic agents and interventions can best be targeted, to prevent corneal graft rejection. Overcoming an unwanted immune response would improve the outcome of corneal transplantation by as much as thirty percent.Read moreRead less
An Open-label Extension Of A Randomised Clinical Trail Of Intravitreal Triamcinolone For Diabetic Macular Oedema
Funder
National Health and Medical Research Council
Funding Amount
$167,733.00
Summary
A 25 fold increase in the risk of going blind on diagnosis of diabetes is one of the most daunting threats that patients face. Most cases of vision impairment in diabetes are due to macular oedema that persists or recurs after laser treatment. There are now a number of uncontrolled, anecdotal reports that intravitreal triamcinolone (IVTA) is highly effective for the treatment of diabetic macular edema which is refractory to conventional laser treatment. We commenced the first placebo-controlled, ....A 25 fold increase in the risk of going blind on diagnosis of diabetes is one of the most daunting threats that patients face. Most cases of vision impairment in diabetes are due to macular oedema that persists or recurs after laser treatment. There are now a number of uncontrolled, anecdotal reports that intravitreal triamcinolone (IVTA) is highly effective for the treatment of diabetic macular edema which is refractory to conventional laser treatment. We commenced the first placebo-controlled, double masked clinical trial of intravitreal triamcinolone for refractory macular oedema in 2002. The 3 month results from this study provide the first scientific proof of principle that intravitreal triamcinolone reduces macular thickness and improves vision. The two year results will be available in March 2005, but confidential interim analysis of efficacy data in September 2004 suggested that the beneficial effect of triamcinolone treatment persisted. Thus it appears that treatment with intravitreal triamcinolone may be the most significant development for the prevention of blindness in people with diabetes since the introduction of laser treatment. It would also be a highly cost-effective intervention that could be administered by general ophthalmologists. The treatment cannot be recommended for routine use, however, until its long term efficacy and safety have been established. Since we already have a well studied group of patients who have received treatment for 2 years, we are in a unique position to extend the study in order to provide the long-term (5-year) safety and efficacy data that does not appear to be forthcoming from any other source. The results of this study will significantly improve knowledge of long-term outcomes of local high dose steroids for diabetic macular oedema, allowing the treatment to be used more rationally. Thus the study is very likely to directly reduce the risk of blindness in people with diabetes.Read moreRead less
Blindness exerts major physical, emotional and economic constraints and hardship upon the sufferer. Transplant surgery can restore vision to many people who are visually impaired as a result of disease affecting the front of the eye. The transplant itself is taken from the eye of a person who has died, after consent from the donor's family. Our goal is to improve the outcome for patients who require transplants of tissue to the front of the eye, in order to restore their vision or to relieve pai ....Blindness exerts major physical, emotional and economic constraints and hardship upon the sufferer. Transplant surgery can restore vision to many people who are visually impaired as a result of disease affecting the front of the eye. The transplant itself is taken from the eye of a person who has died, after consent from the donor's family. Our goal is to improve the outcome for patients who require transplants of tissue to the front of the eye, in order to restore their vision or to relieve pain. Our work is predicated on the finding that unwanted immune responses are the major cause of graft failure in such patients. The recipient recognizes the grafted tissue as being foreign, and rejects it. Treatment with conventional systemic drugs appears to hold little promise for further improvements in outcome, but gene therapy applied to the donor tissue may provide a safe and effective way of reducing transplant failure. Gene therapy can be undertaken on the donor tissue in the laboratory, prior to transplantation surgery. In this project, we will assess the suitability of a new method of modifying the transplant. All of the work will be performed on the laboratory bench, or in experimental animals.Read moreRead less
Therapeutic Control Of Pathological Myopia: Role Of Transforming Growth Factor-beta
Funder
National Health and Medical Research Council
Funding Amount
$312,730.00
Summary
Myopia (shortsightedness) is due to the eye being too long. It is a common refractive disorder, affecting some 25-30% of people in developed countries, and results in blurred distance vision. The optical consequences of myopia, namely blurred distance vision, are correctable with spectacles or contact lenses. However, a significant minority of individuals (3% of the Australian population) have excessively long eyes and high amounts of myopia. These enlarged eyes impose abnormal stresses on the s ....Myopia (shortsightedness) is due to the eye being too long. It is a common refractive disorder, affecting some 25-30% of people in developed countries, and results in blurred distance vision. The optical consequences of myopia, namely blurred distance vision, are correctable with spectacles or contact lenses. However, a significant minority of individuals (3% of the Australian population) have excessively long eyes and high amounts of myopia. These enlarged eyes impose abnormal stresses on the structures inside, particularly affecting the retina, which is the light sensitive part of the eye. Damage that occurs to the retina in these eyes is, at present, untreatable and irreversible and can result in blindness. Myopia is the 2nd leading cause of blindness amongst adults of working age. For the eye to grow so large, its white outer coat (the sclera) must expand without allowing any leaks of the delicate structures and fluids inside. Although the sclera gets very thin as it expands, it has been shown that this process of expansion is a biochemically active process and not due to passive stretch. Before elongation of the eye can occur the biochemical structure of the sclera must change, a complex process involving accelerated production and breakdown of the biochemical building blocks of the sclera. Previous research in our laboratory indicates that changes in structure of the sclera are associated with reduced levels of the growth-controlling protein transforming growth factor-beta (TGF-beta). The aim of this project is to supplement TGF-beta levels in the sclera in order to reverse the loss of scleral tissue, stop the development of myopia and, therefore, prevent the development of the sight-threatening pathology associated with high myopia. In addition, we will determine the most effective way to deliver a sustained dose of TGF-beta to the sclera.Read moreRead less
Regulation Of Lens Cell Behaviour By RTK Antagonists, Sef And Sprouty.
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
Cataract, the loss of transparency of the eye lens, is a major cause of world blindness. A cure for cataract depends on a better understanding of the molecular processes in the normal and cataractous lens. Lens growth is regulated by controlled proliferation of epithelial cells and their localised differentiation into fibres. As disruption to this tight regulation leads to cataract, identifying the molecules that control cell proliferation and differentiation will provide insights into the mecha ....Cataract, the loss of transparency of the eye lens, is a major cause of world blindness. A cure for cataract depends on a better understanding of the molecular processes in the normal and cataractous lens. Lens growth is regulated by controlled proliferation of epithelial cells and their localised differentiation into fibres. As disruption to this tight regulation leads to cataract, identifying the molecules that control cell proliferation and differentiation will provide insights into the mechanisms involved in cataract formation. Following cataract surgery, for example, many patients develop aftercataract which results from residual lens cells. These residual cells, unlike those tightly regulated in the normal lens, divide and differentiate to form a secondary cataract. The main aim of this study is to understand what molecules regulate the proliferation and differentiation of lens cells. Growth factors are key regulators of cell behaviour and our studies provide evidence that FGF growth factors play pivotal roles in the lens by influencing cell proliferation and differentiation. We have recently identified inhibitors of FGF in the lens, called Sprouty and Sef; molecules shown in other systems to effectively block FGF intracellular signalling pathways. To understand how Sef and Sprouty regulate lens cell proliferation and fibre differentiation, we plan to examine what regulates their expression, and more importantly their role in FGF-induced cell signalling in normal lens biology. To do this, we will use a well established explant culture system to monitor the effectiveness of these endogenous inhibitors on growth factor-induced lens cell proliferation and differentiation, as well as use transgenic mice technology to determine the role they play in situ. By understanding the molecular and cellular processes essential for normal lens development, we can better understand how disruptions of these processes lead to cataract formation.Read moreRead less