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
Regulation Of The Cardiovascular Disease-Associated Protease Inhibitor Cystatin C For Therapeutic Application
Funder
National Health and Medical Research Council
Funding Amount
$498,505.00
Summary
Proteases can contribute to atherosclerosis, so they are normally controlled by the endogenous inhibitor, Cystatin C (Cst C). Some conditions cause reduction in Cst C levels and hence disease. On the other hand, excess Cst C can form toxic aggregates. In this project, we will identify mechanisms controlling Cst C expression and aggregation to find therapeutic strategies to treat cardiovascular diseases associated with Cst C.
Regulation Of Synthesis, Dimerisation And Secretion Of The Amyloidogenic Protease Inhibitor Cystatin C
Funder
National Health and Medical Research Council
Funding Amount
$423,565.00
Summary
The cells that compose our tissues are embedded in a complex mesh of extracellular proteins (for example collagen) that provide support, strenght and elasticity to the tissues. This extracellular matrix is not static; it is constantly remodelled when, for example, the cells of the immune system move through interstitial spaces to monitor the healthiness of the tissues. When infections or injuries occur, the inflammatory reactions that develop, and the processes involved in tissue repair, also in ....The cells that compose our tissues are embedded in a complex mesh of extracellular proteins (for example collagen) that provide support, strenght and elasticity to the tissues. This extracellular matrix is not static; it is constantly remodelled when, for example, the cells of the immune system move through interstitial spaces to monitor the healthiness of the tissues. When infections or injuries occur, the inflammatory reactions that develop, and the processes involved in tissue repair, also involve profound changes in the composition of the extracellular matrix. Such processes are also important for tumour growth; the cancer cells need to clear their way through interstitial space to escape to circulation and metastasize. During all these processes, the cells release to the extracellular space proteases that degrade collagen and the other components of the extracellular matrix. Obviously, these proteases must be tightly regulated to prevent them running out of control, so the cells also produce inhibitors of the proteases. The amount of proteases and inhibitors contained in the extracellular space must be maintained properly. If this equilibrium is disrupted, this can lead to pathology For instance, atherosclerosis is caused in part by excessive proteolysis of the blood vessel wall. In this project we want to study the mechanisms of one of the most abundant and important inhibitors of extracellular proteolysis: Cystatin C. We have discovered that certain cells of the immune system called dendritic cells posses interesting mechanisms to regulate how much Cystatin C they secrete. Furthermore, one of this mechanisms, which consists of pairing the protein to produce inactive dimers, may be the cause of some diseases characterised by accumulation of Cystatin C in the extracellular space. Our study may allow us to design therapies for the treatment of pathologies associated with defective or excessive production of Cystatin C.Read moreRead less
The Activation Of Lipoprotein Lipase By Apolipoprotein C-II
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a h ....Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a high blood-lipids that can lead to premature atherosclerosis. Regulation of lipoprotein lipase occurs via an interaction with the regulatory protein apolipoprotein C-II. Individuals with apolipoprotein C-II deficiency also exhibit abnormal plasma lipid levels with an associated increased risk of coronary heart disease. These considerations demonstrate that the activation of lipoprotein lipase by apolipoprotein C-II is pivotal to the maintenance of normal blood lipid levels. The present proposal will establish the structure and orientation of apolipoprotein C-II in a lipid environment and provide a structural model for the activation of lipoprotein lipase by apolipoprotein C-II. These molecular details will serve as a model for the regulatory interactions of other apolipoproteins within lipoprotein particles and will generate leads for the development of new strategies for the treatment of blood lipid irregularities.Read moreRead less