Generation And Characterisation Of An Animal Model For Age-related Macular Degeneration
Funder
National Health and Medical Research Council
Funding Amount
$226,650.00
Summary
Age-Related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the aged population in the developed world, and it is one of the least understood retinal diseases. AMD is a slow, progressive and painless condition that affects the macula, the small central part of the retina that allows one to see fine detail clearly. With the ever-increasing human life expectancy, the prevalence of AMD (15-30%) in the age group of over 75 years will significantly increase, causing enorm ....Age-Related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the aged population in the developed world, and it is one of the least understood retinal diseases. AMD is a slow, progressive and painless condition that affects the macula, the small central part of the retina that allows one to see fine detail clearly. With the ever-increasing human life expectancy, the prevalence of AMD (15-30%) in the age group of over 75 years will significantly increase, causing enormous social and financial problems for the community. In spite of the significance of this problem, the exact cause of AMD is not yet known, and there is no permanent effective treatment or cure for the condition. One of the major obstacles hindering any advances towards the development of intervention strategies or therapies is the lack of an appropriate animal model. Currently, the animal models that are available for ocular diseases do not fit the human AMD situation. This project aims to characterize the first animal model for retinal degeneration caused by abnormal functioning of the retinal pigment epithelial cells (RPE). The main role of RPE cells is the phagocytosis and digestion of the continuously growing and shed light receptor segments in the eye. Their normal functioning therefore is vital to maintaining good vision. The availability of such an animal model will allow us to learn more about the changes that might occur in the eye leading to the development of AMD and to design strategies to prevent or delay progression of the condition.Read moreRead less
The Role Of Collagenase (MMP-1) In The Pathogenesis Of Human Pterygia
Funder
National Health and Medical Research Council
Funding Amount
$246,100.00
Summary
Pterygia are a common, recurrent, disfiguring, and sight-threatening disease of the human eye. This disease is extremely common world wide and particularly in the Australian aboriginal population. The triggers for this disease are unknown. Prolonged exposure to environmental elements, such as ultra violet (UV) light, is proposed to be the main initiating factor. Our previous studies have shown the important role played by a family of proteolytic enzymes (metalloproteinases) in the progressive an ....Pterygia are a common, recurrent, disfiguring, and sight-threatening disease of the human eye. This disease is extremely common world wide and particularly in the Australian aboriginal population. The triggers for this disease are unknown. Prolonged exposure to environmental elements, such as ultra violet (UV) light, is proposed to be the main initiating factor. Our previous studies have shown the important role played by a family of proteolytic enzymes (metalloproteinases) in the progressive and invasive nature of pterygia. We have significant preliminary evidence that a large percentage of patients with pterygia carry a mutation in one of these enzymes (collagenase-1). This is the most abundant enzyme expressed in pterygium tissue and probably plays a major role in invasion and progression in this disease. UV light activates cells in pterygia to induce expression of collagenase-1. This study will determine whether or not people with a genetic predisposition are more likely to develop pterygia and whether or not environmental factors, such as UV light, trigger progression of disease. If this is the case, then subjects with this genetic predisposition would be at increased risk for the development of pterygia (and their complications) and could be advised to take preventative measures to minimize the risk of developing this disease.Read moreRead less
Probing UDP-glucuronosyltransferase Protein-protein Interactions: The Power Of Two.
Funder
National Health and Medical Research Council
Funding Amount
$482,710.00
Summary
Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransfera ....Drugs and other chemicals (eg. dietary constituents, environmental pollutants, and chemicals that occur naturally in the body - such as steroid hormones) are broken down by specialised proteins called enzymes. This process is referred to as biotransformation, or 'metabolism'. Drug and chemical metabolism serves as a detoxification mechanism (since the products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. UDP-Glucuronosyltransferase (UGT) is one of the most important enzymes involved in drug and chemical metabolism. Consistent with its ability to metabolise such a large number of compounds, UGT is known to exist as a 'superfamily' of structurally related proteins. Despite the importance of UGT, little is known about the structural characteristics of these enzymes that are responsible for recognising and binding different classes of chemicals. Accumulating evidence from this and other laboratories indicates that the individual UGT proteins may combine with themselves (to form a homodimer) and with other UGT proteins (to form heterodimers). This project largely seeks to define the scope of UGT homo- and hetero- dimerisation, identify the structural elements of the proteins responsible for association and characterise the functional significance of dimerisation. The project will further explore associations between UGTs and other proteins, namely albumin. Characterisation of UGT dimerisation and associations with other proteins is fundamental to our understanding of how this enzyme functions and selects particular chemicals for metabolism. The work also has important implications for the devlopment and interpretation of in vitro (or 'test-tube') approaches for predicting how drugs are metabolised in humans. Such tests are widely employed in research and pharmaceutical company laboratories to predict how the body 'handles' new drugs prior to their administration to humans.Read moreRead less
The Molecular Mechanism Of Sphingosine Kinase Activation
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Many cell processes like growth, death and differentiation are controlled by hormones and other molecules that interact with receptors on the outside of the cell. When this type of molecule binds to a receptor, it often triggers the production of signaling molecules inside the cell that initiate a change in the cells behaviour. The lipid molecule, sphingosine phosphate has been identified as such a signaling molecule that appears to be involved in the regulation of a diverse array of important m ....Many cell processes like growth, death and differentiation are controlled by hormones and other molecules that interact with receptors on the outside of the cell. When this type of molecule binds to a receptor, it often triggers the production of signaling molecules inside the cell that initiate a change in the cells behaviour. The lipid molecule, sphingosine phosphate has been identified as such a signaling molecule that appears to be involved in the regulation of a diverse array of important mammalian cellular processes. Recent studies have found that sphingosine phosphate is involved in the inflammation of cells, and if its production can be blocked, inflammation is not seen. Therefore, this provides a potential target for therapeutic intervention in the inflammation process. However, the manner by which cells regulate sphingosine phosphate levels is not well known. It is known that sphingosine phosphate is produced by the enzyme sphingosine kinase, and strong evidence suggests that changes in this enzyme's activity in the cell regulate sphingosine phosphate levels. However, how the cell changes the levels of sphingosine kinase activity is completely unknown. This study will investigate this problem with the view that understanding this process will allow the development of new drugs to block increases in sphingosine kinase activity, preventing increases in sphingosine phosphate levels, and it turn, preventing cellular inflammation.Read moreRead less