The Mechanism Of Action Of Muscarinic Receptor Antagonists In Preventing Axial Myopia
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Myopia (short-sightedness) is the most common refractive error and is due to the eye being too long and, if uncorrected, results in blurred distance vision. Approximately 30% of the population in developed countries, such as Australia, suffer from myopia. In a significant minority of individuals with high degrees of myopia, it is a sight threatening condition and a leading cause of blindness. It has been found that the pharmacological agent, atropine, is effective in preventing myopia in childre ....Myopia (short-sightedness) is the most common refractive error and is due to the eye being too long and, if uncorrected, results in blurred distance vision. Approximately 30% of the population in developed countries, such as Australia, suffer from myopia. In a significant minority of individuals with high degrees of myopia, it is a sight threatening condition and a leading cause of blindness. It has been found that the pharmacological agent, atropine, is effective in preventing myopia in children and in animal models of myopia. However the side effects of blurred vision at near, glare from dilated pupils and the unknown long term effects of chronic atropine treatment have prevented this approach to myopia control from becoming an established treatment in children. It was originally thought that the drug worked by preventing the eye from accommodating for near objects, however it has now been shown that atropine does not to work by this mechanism, but rather by another non-accommodative mechanism. The aim of this project is to determine the mechanism of action of this class of drugs (known as muscarinic antagonists) in preventing myopic eye growth. The project will investigate in which ocular tissues the various subtypes of muscarinic receptors sensitive to these drugs are located and how these are changed in myopic eyes. It will also determine the specific receptor subtype these drugs act on and whether these drugs inhibit eye growth in myopia by altered retinal signalling activity. The results from this study will elucidate the mechanism and route of action of muscarinic antagonists in preventing myopic eye growth. These findings will advance the probability of developing an effective selective muscarinic antagonist drug to use for the prevention of axial myopia without the side effects associated with the broad-band antagonist atropine. The development of such drugs will have a major economic benefit to the Australian population.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
Control Of Refractive Error Through Ionically Driven Fluid Movements
Funder
National Health and Medical Research Council
Funding Amount
$208,600.00
Summary
Myopia affects about half the world's population with recent studies suggesting epidemic proportions among some Asian schoolchildren though we are not seeing this in Australia. Costs associated with detection, monitoring and optical correction of low and high myopia are huge. High myopes (15% with > 6D) also have a greatly increased risk of blindness between the ages of 30 and 50 years due to secondary disorders associated with impaired fluid balance (retinal and choroidal oedema, macula oede ....Myopia affects about half the world's population with recent studies suggesting epidemic proportions among some Asian schoolchildren though we are not seeing this in Australia. Costs associated with detection, monitoring and optical correction of low and high myopia are huge. High myopes (15% with > 6D) also have a greatly increased risk of blindness between the ages of 30 and 50 years due to secondary disorders associated with impaired fluid balance (retinal and choroidal oedema, macula oedema, retinal detachment and glaucoma). Currently there is no accepted pharmaceutical treatment for myopia though our studies in chick have provided the theoretical rationale and experimental data for a potential therapy and patent. This patent is now at the PCT stage and attests that changes in the abundance of the ions of the subretinal space control fluid movements across the retina to choroid and can be modulated therapeutically by diuretics to control fluid flow and hence axial growth and myopia. This application aims to take our current knowledge about fluid control in myopic chick into a mammalian model prior to preclinical trials in monkey. We anticipate it will take 1 year to establish the feasibility of diuretic control of experimentally induced myopic refractive errors in guinea pigs and the best drug and best the dosage range. These studies will contribute to the scientific understanding and bring the proposed pharmaceutical therapy for myopia in adults and children to a point of full commercialization. We believe that the results found in chick will have significance for early and late-onset myopia in humans as it is highly likely that the same mechanisms of ocular growth regulation operate throughout life.Read moreRead less
A National Resource For Mouse Models Of Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$483,643.00
Summary
Mouse models of mesothelioma have led to a greater understanding of the disease and the identification of potential drug therapies some of these have now been translated into clinical trials. In the existing models, mesothelioma cells that have been grown in the laboratory are transplanted into animals by injecting the cells under the skin. Different cell lines with different properties are used in different experimental protocols. This application will fund the establishment of a central resour ....Mouse models of mesothelioma have led to a greater understanding of the disease and the identification of potential drug therapies some of these have now been translated into clinical trials. In the existing models, mesothelioma cells that have been grown in the laboratory are transplanted into animals by injecting the cells under the skin. Different cell lines with different properties are used in different experimental protocols. This application will fund the establishment of a central resource to maintain and distribute these cell lines. In addition, we describe a new transgenic mouse model in which mesotheliomas are rapidly induced in the peritoneal cavity after exposure to asbestos, recreating the natural tumour development much more accurately. These mice have been engineered to express the cancer causing protein of a monkey virus (SV40 large T antigen) in their mesothelial cells because it has been suggested that the virus has a role in the development of mesothelioma. This application also seeks funding to use the MexTAg mice to test the usefulness of different therapies for the prevention or treatment of mesothelioma. These animals give us the ability to investigate the disease in a more realistic environment than previous models. In parallel collaborative studies with other groups investigating different aspects of the biology of this cancer, we plan to analyze the earliest changes in the development of the disease and search for early markers using proteomics and gene expression studies. We anticipate that this model will generate information more directly relevant to understanding the human disease and will provide essential experimental data for clinical trials.Read moreRead less
Physiological Mechanisms Of Efficacy Of Cervical Flexor Muscle Retraining
Funder
National Health and Medical Research Council
Funding Amount
$264,750.00
Summary
Neck pain is a significant problem in society and its frequency is beginning to match the proportions of back pain, probably reflecting our increasingly sedentary lifestyles. Several problems have been identified in the muscle system in persons who suffer from neck pain. Therapeutic exercise has been found to have benefit in preventing and relieving pain and improving the neck function. Currently there are several, quite different methods of exercise and there is controversy regarding how therap ....Neck pain is a significant problem in society and its frequency is beginning to match the proportions of back pain, probably reflecting our increasingly sedentary lifestyles. Several problems have been identified in the muscle system in persons who suffer from neck pain. Therapeutic exercise has been found to have benefit in preventing and relieving pain and improving the neck function. Currently there are several, quite different methods of exercise and there is controversy regarding how therapeutic exercise works. It has been argued that parameters such as changes in muscle strength, endurance, joint position sense or muscle coordination may be responsible for the clinical efficacy. It is difficult to disentangle the effective component of exercise strategies and thus prescribe the most effective exercise strategies. This series of experiments will evaluate the physiological factors that change with a specific exercise intervention and to compare different exercise modalities in order to identify the most effective means to induce these changes. Cervical muscle training, using a proven exercise intervention strategy for chronic neck pain and headache, has been chosen as the model to investigate these questions. This exercise strategy has been chosen not only because it has been shown to be effective, but also because it does not conform to contemporary rationales for strength or endurance training. Thus while effective in relieving pain, it is unlikely to produce changes in these parameters. Thus other mechanisms are likely to be responsible for the clinical change. This research stands to make a significant contribution to exercise therapeutics by identifying the effective components of different exercise methods and investigating the pain relieving effects of the specific exercise. This knowledge will lead to the construction of a research based exercise program for neck pain patients, rather than have the current situation of often arbitrary choice of exercise.Read moreRead less
A Pharmacological Targeting Approach Implementing Albumin As A Carrier Of A Novel Chemotherapeutic
Funder
National Health and Medical Research Council
Funding Amount
$560,659.00
Summary
New drugs for cancer therapy are essential to develop that overcome resistance to standard chemotherapeutics. We have developed potent anti-cancer chelators that bind to the abundant plasma protein, albumin. Our studies showed increased tumour cell uptake of the chelator, Dp44mT, mediated by albumin. We will elucidate the mechanisms of their albumin-mediated uptake, with the aim to implement albumin nanoparticles as carriers of novel chelators to selectively target tumours.
A Pharmacological Targeting Approach Implementing Albumin As A Carrier Of A Novel Chemotherapeutic
Funder
National Health and Medical Research Council
Funding Amount
$428,065.00
Summary
Novel agents that bind essential metals have emerged as a potential avenue for cancer therapy. My laboratory has developed potent anti-cancer agents, such as Dp44mT, that bind to the plasma protein, albumin. Notably, the uptake of Dp44mT into tumour cells was increased in the presence of albumin. My research will examine the mechanisms in the albumin-mediated increase in Dp44mT uptake into tumour cells, with the goal to develop albumin nanoparticles to selectively deliver our agents to tumours.
Validating The NLRP3 Inflammasome As A Therapeutic Target In Motor Neuron Disease
Funder
National Health and Medical Research Council
Funding Amount
$780,249.00
Summary
There is no effective treatment for Motor Neuron Disease (MND). Two Australian’s die each day from MND, and 2 more are diagnosed. Modification of the immune system is one potential means of slowing MND. Our research team has identified a component of the immune system, which may be an ideal therapeutic target to treat this disease. Our project will test this therapeutic target in animal models of MND, and in human MND blood samples.
Robotic Surgical System For Image Guided Non-invasive Focused Ultrasound Induced Ablation Of Liver Cancers
Funder
National Health and Medical Research Council
Funding Amount
$582,231.00
Summary
According to National Cancer Institute, liver and bile duct cancers are the fifth most common cancer in men and the seventh in women. Due to poor prognosis involving surgery, radiotherapy and chemotherapy, our aim is to develop a novel image-guided, radiation-free, non-invasive robotic HIFU system with means for compensation of organ movement during treatment. The objective is to produce damage to the target in a predictable and reproducible manner while sparing overlying surrounding tissues.