We have discovered that activating a cell surface protein increases blood sugar levels in mice. This might occur in diabetes and liver disease. We plan to (1) learn which activators of this protein increase glucose; (2) understand how they affect glucose metabolism; (3) study new inhibitors of this protein for blocking increased glucose production; (4) test the potential therapeutic benefits of blocking this protein in mouse models of type 2 diabetes and non-alcoholic fatty liver disease.
Defining The Function Of The Thrombin Receptor, PAR4, On Human Platelets
Funder
National Health and Medical Research Council
Funding Amount
$541,402.00
Summary
Inappropriate blood clot formation is the cause of most heart attacks and strokes, and platelets are the cells in the blood which form these clots. Drugs that block platelet function, such as aspirin, are used to prevent heart attack and stroke but are frequently ineffective. We will study the signals which control platelet incorporation into clots in order to discover improved therapeutic strategies for heart attack and stroke prevention.
Proof-of-concept Studies For A Novel Anti-thrombotic Agent
Funder
National Health and Medical Research Council
Funding Amount
$632,352.00
Summary
Blood clots cause most heart attacks and strokes, and platelets are the blood cells that form these clots. Drugs that block platelet function, such as aspirin, are used to prevent heart attack and stroke but are frequently ineffective. Here, we will develop a new drug that prevents platelet incorporation into blood clots, that will be suitable for the prevention of heart attack and stroke in humans, and that may improve on existing therapies.
Cellular Contributions To PAR-2's Essential Role In Periodontal Disease
Funder
National Health and Medical Research Council
Funding Amount
$648,786.00
Summary
Periodontal disease is a disease of the gums, which ultimately causes loss of teeth. It is a debilitating condition affecting about 20% of Australian adults. PAR-2, a receptor for protein-degrading enzymes, which is present on cells in the gums, is known to be required for development of the disease. This project will investigate the mechanism of PAR-2’s involvement in periodontal disease and provide ideas for development of treatments.
Targeting Protease Activated Receptor 2 In Immunometabolism And Obesity
Funder
National Health and Medical Research Council
Funding Amount
$720,760.00
Summary
New approaches to prevent and treat obesity and metabolic diseases are National Health Priorities. Obesity is now recognised as an inflammatory disease. This project seeks new biomedical information to verify a new hypothesis that a protein (PAR2) on the surface of fat cells and immune cells is associated with the development of obesity and metabolic disorders.
Chikungunya Virus Disease; The Role Of Proteases And Their Receptors
Funder
National Health and Medical Research Council
Funding Amount
$682,716.00
Summary
Chikungunya virus (CHIKV) is a mosquito borne virus related to the Australian Ross River virus. The arthritic disease caused by these viruses is often poorly managed by current treatments. We have recently identified several proteins call proteases that circulate in the blood of infected people and promote arthritis. If successful the grant will provide new treatment options for these (and perhaps other) diseases using recently developed drugs that inhibit the activity of these proteases.
Protease Activated Receptor 2 Antagonist In Inflammatory Disease
Funder
National Health and Medical Research Council
Funding Amount
$621,347.00
Summary
The immune response to infection involves a network of proteins that produce an inflammatory response. Sometimes this response is prolonged or uncontrolled and can lead to a large number of inflammatory and other diseases. We have discovered a class of drugs that can bind to a particular protein on the surface of human cells and control this inflammatory response. This property has the potential to treat a wide range of inflammatory and other diseases in humans.
THE ROLE OFPROTEASES AND PROTEASE ACTIVATED RECEPTORS IN RESPIRATORY EPITHELIAL CELL FUNCTION IN ASTHMA
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
The epithelium lines the airways and is, therefore, constantly exposed to a variety of exogenous antigens, infectious agents and noxious stimuli. This tissue responds to such stimuli by secreting substances that help counteract the insult while simultaneously initiating healing and repair. In this proposal, we will investigate the role of a group of receptors present on the surface of the epithelium which monitor the area surrounding the epithelium for the presence of enzymes which digest host t ....The epithelium lines the airways and is, therefore, constantly exposed to a variety of exogenous antigens, infectious agents and noxious stimuli. This tissue responds to such stimuli by secreting substances that help counteract the insult while simultaneously initiating healing and repair. In this proposal, we will investigate the role of a group of receptors present on the surface of the epithelium which monitor the area surrounding the epithelium for the presence of enzymes which digest host tissue or pathogens. These receptors, known as PAR, sense their suroundings by binding the protease, a process which then triggers the cell to respond in an appropriate way by releasing cytokines and mediators. There are 4 PAR, each with different properties, and are present on many cells of the body. However, little information about their role on epithelium exists. Although we have shown them to be upregulated in the epithelium in the socio-economically important disease, asthma, their function in this disease remains elusive. We will, therefore, initiate studies to define their role in inflammation, healing and repair as this information may lead to a better understanding of their role in disease which may then translate into better treatment.Read moreRead less
Influence Of Endothelin And Protease-activated Receptors On Eosinophil Trafficking In The Airways Of Allergic Mice
Funder
National Health and Medical Research Council
Funding Amount
$376,980.00
Summary
Asthma is a chronic inflammatory lung disease. This disease affects about 10% of the population, although its incidence in primary school-age children is as high as 30% in some cities. People suffering from asthma have very responsive (hyperresponsive) airways to substances which are usually innocuous. Many asthmatics are allergic to substances such as pollens, animal dander and house dust, which causes the airways of the asthma sufferer narrow, making breathing more difficult. The airways of as ....Asthma is a chronic inflammatory lung disease. This disease affects about 10% of the population, although its incidence in primary school-age children is as high as 30% in some cities. People suffering from asthma have very responsive (hyperresponsive) airways to substances which are usually innocuous. Many asthmatics are allergic to substances such as pollens, animal dander and house dust, which causes the airways of the asthma sufferer narrow, making breathing more difficult. The airways of asthma sufferers also become inflamed and the resulting swelling of the airways and excess formation of mucous makes breathing difficult. Inflamed asthmatic airways contain large numbers of cells called eosinophils, which move from the blood into the airways. Substances released from the eosinophils are thought to damage the airways and cause airways hyperresponsiveness. We have developed a mouse model of allergic inflammation which has many of the hallmark features of asthma, including high numbers of eosinophils and hyperresponsive airways. We have recently shown that these effects are inhibited by treatment of allergic mice with a drug called SB217242. SB217242 inhibits the actions of endothelin, a peptide that is produced in elevated amounts in the airways of asthma sufferers and which may produce many of the effects associated with asthma. We wish to investigate the mechanisms through which SB217242 and drugs which stimulate novel protease-activated receptors inhibits the increase in eosinophil numbers in the airways. We will investigate the possibility that these drugs inhibit the migration of eosinophils from the blood into the airways, using a unique microscope that allows us to visualize the movement of eosinophils into tissues such as the airways. These studies are likely to be of considerable strategic value in determining the potential usefulness of these drugs in the treatment of asthma.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