Therapeutic Targeting Of CD40L-Mac-1 In Inflammatory Disease, In Particular Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$559,642.00
Summary
Atherosclerosis is a major burden for human health resulting in myocardial infarction-stroke. We have previously identified a novel interaction between two adhesion molecules, CD40L and Mac-1, which mediates leukocyte adhesion to endothelial cells being a major determinant of atherosclerotic plaque development. We are now developing blocking peptides and recombinant antibodies thereby exploring various anti-inflammatory- anti-atherosclerotic strategies, targeting both Mac-1 and CD40L.
Development Of Specific Inhibitors Of Parasitic Enzymes
Funder
National Health and Medical Research Council
Funding Amount
$199,413.00
Summary
Parasitic diseases such as malaria, schistosomiasis, filariasis, leishmaniasis, and american trypanosomiasis (Chaga?s disease) are a significant public health issue, especially in tropical and subtropical regions of the world. In children, they cause death or impaired growth and in adults debilitating chronic illness. These parasitic infections are increasingly being recognized as responsible for chronic illness in many industrialized countries as well. There are no vaccines currently available ....Parasitic diseases such as malaria, schistosomiasis, filariasis, leishmaniasis, and american trypanosomiasis (Chaga?s disease) are a significant public health issue, especially in tropical and subtropical regions of the world. In children, they cause death or impaired growth and in adults debilitating chronic illness. These parasitic infections are increasingly being recognized as responsible for chronic illness in many industrialized countries as well. There are no vaccines currently available for the treatment of any of the human parasitic infections. In addition, the drugs that are currently used are becoming less effective because of the spread of drug resistant strains. Schistosomiasis, is the second most prevalent parasitic disease, after malaria, and is a leading cause of severe morbidity and death in many parts of the world. The disease is caused by flatworms or blood flukes, the eggs of which indirectly cause damage to the liver and spleen of infected individuals. These parasites feed on human red blood cells and use hemoglobin as their major food source. Our collaborative team (Brindley, Abbenante, Fairlie) has identified two enzymes that these flatworms need to use to eat red blood cells. This project aims to develop compounds that will stop these enzymes from functioning. These compounds will be tested to see whether they can cause the parasites to die of starvation. If successful these new compounds can be used as drugs to treat the disease and the general strategy can be applied to other blood-feeding parasites.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
Relaxin family peptides are small proteins that have numerous essential biological roles in the vascular system, brain and gut. The hormone relaxin is currently in Phase III clinical trials to treat heart failure and the other peptides show great potential as drugs to treat diseases including mental illnesses and obesity. My research focuses on developing drugs targeting the receptors for these important peptide systems and understanding how these drugs can be best used therapeutically
Novel Candidate Genes, Lung Function And Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
We propose to study airway remodelling (structural changes to the airway) and in asthma using human samples and rodent models of asthma. We are particularly interested in investigating the role of trefoil peptide 2 and relaxin, two genes identified as determining lung function. To do this we need to understand the mechanisms of airway remodelling and its impact on disease severity in the patient. A strength of this study is availability of samples from a large study of human asthma.
The Bcl-2 family of proteins is crucial for apoptosis (a form of programmed cell death) regulation. They target the mitochondrial outer membrane where they interact to determine cell fate. We will evaluate the membrane interactions of the Bcl-2 proteins in complementary biophysical and cellular experiments to redefine our understanding of the mechanism of apoptosis and provide new avenues for the development of compounds to selectively modulate diseases in which apoptosis is unregulated.
Development Of Selective Melanocortin Receptor Agonists And Antagonists
Funder
National Health and Medical Research Council
Funding Amount
$684,607.00
Summary
Human melanocortin receptors play a key role in a variety of physiological processes ranging from energy regulation, skin pigmentation and regulation of food intake. This project aims to generate novel peptide based molecules that will selectively interact with different melanocortin receptors to better understand their pharmacology thereby opening the potential for future drug development for obesity, stroke or inflammatory skin disorders.
I am a physiologist with expertise in endocrinology determining the roles of particular regulatory peptides in the normal functions of the gastrointestinal tract and in the development of gastrointestinal, renal and prostate cancers.
Potent Small Molecule Modulators Of A Complement Protein In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$689,428.00
Summary
We have invented powerful new compounds that act on the cell surface and regulate inflammation. We plan to (1) fine-tune our small molecules for optimal activity on different kinds of immune cells; (2) understand mechanisms by which the compounds affect cellular inflammatory responses; (3) evaluate the compounds as potential treatments in rodent models of inflammatory diseases implicated from cell studies. This study is anticipated to lead to clinical studies for a new kind of drug treatment.