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
Design And Development Of Small Molecules To Regulate Protease Activated Receptor Type 2
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
A new class of proteins have been discovered on the surface of cells. These are activated by enzymes known as proteases and are therefore called Protease Activated Receptors (PARs). PARs appear to be very important 'sensors' of proteases outside cells, becoming activated in response to very low concentrations of proteases. This suggest that proteases may exert some of their biological effects through these receptors, which are now implicated in a growing number of diseases (e.g. thrombosis, card ....A new class of proteins have been discovered on the surface of cells. These are activated by enzymes known as proteases and are therefore called Protease Activated Receptors (PARs). PARs appear to be very important 'sensors' of proteases outside cells, becoming activated in response to very low concentrations of proteases. This suggest that proteases may exert some of their biological effects through these receptors, which are now implicated in a growing number of diseases (e.g. thrombosis, cardiovascular disorders, asthma, inflammatory bowel disease, Crohn's disease, pancreatitis, stomach and colon cancer, arthritis, and there may also be a role in wound healing). We are working towards dissecting the roles for one of these receptors (PAR2) in disease by developing small molecules for selective binding to this receptor. We will particularly distinguish between compounds that can activate (agonists) or deactivate (antagonists) the receptor. These experiments will involve computer-assisted compound design, structural comparisons between small molecules with activity and those without, and cellular studies designed to measure affinity, activation and deactivation of PAR2. The outcome will be a series of small molecules that bind tightly to the PAR2 receptor and have a well defined function (antagonist, agonist, partial agonist). While the above studies are in progress some peptides that are known to activate this receptor will be examined in rodent models of human disease (airways inflammation, pancreatitis, stomach and colon cancer, arthritis). Studies like this have been very revealing for us in the past (Nature 1999, 398, 156-160 A protective role for protease-activated receptors in the airways). Then the designed and developed compounds will also be examined for signs of therapeutic potential. The work will provide a better understanding of how this receptor works and a clearer picture of the role of this receptor in human disease.Read moreRead less
Alternate Splicing Of Tryptase Genes Regulates Their Specificity
Funder
National Health and Medical Research Council
Funding Amount
$294,250.00
Summary
Tryptases are enzymes implicated in inflammatory disorders including arthritis, inflammatory bowel disease (IBD) and asthma. Specific tryptase inhibitors are effective in treating these diseases. We have discovered that each human tryptase gene is processed into two different protein products via a mechanism called alternate splicing. We will investigate the structure and function of these.
Post-translational Control Of Indoleamine 2,3-dioxygenase
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
It is apparent that a protein called indoleamine 2,3-dioxygenase is important for controlling the immune system of relevance to various normal and disease conditions including pregnancy, cancer, inflammation, infectious disease and autoimmunity. Despite this little is known about how this important protein is controlled. The aim of this project is to better understand how this protein is regulated that can highlight ways in which to alter the enzymes activity to modulate immune responces.
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.