REGULATION OF GLUCOCORTICOID SENSITIVITY BY ANNEXIN-1
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
Steroids like prednisolone or cortisone are very effective at reducing inflammation in diseases like rheumatoid arthritis and are particularly known to decrease substances involved in inflammation. Almost 70% of patients with rheumatoid arthritis are treated more or less continuously with steroids. Steroid resistance (need for higher doses) or changes in steroid-sensitivity has been widely recognized in asthma, inflammatory bowel disease, and rheumatoid arthritis. Many new drug therapies however ....Steroids like prednisolone or cortisone are very effective at reducing inflammation in diseases like rheumatoid arthritis and are particularly known to decrease substances involved in inflammation. Almost 70% of patients with rheumatoid arthritis are treated more or less continuously with steroids. Steroid resistance (need for higher doses) or changes in steroid-sensitivity has been widely recognized in asthma, inflammatory bowel disease, and rheumatoid arthritis. Many new drug therapies however have the aim of keeping cortisone use to a minimum because of undesirable side effects like osteoporosis. Annexin-1 is an anti-inflammatory substance important in arthritis development which is also known to mediate many of the actions of steroids. However, the possible contribution of annexin-1 to mediate the effect of steroids in the regulation of these substances has not been examined. Moreover, how annexin-1 turns genes on is not known. Our studies will therefore reveal whether the absence of annexin-1 will increase inflammatory substances turn genes, and secondly, by determining the possible substances regulated by annexin-1 if the treatment with steroids are less effective in the absence of annexin-1. If annexin-1 is found either to increase anti-inflammatory substances or to mediate the effect of therapeutic steroids, its capacity to be involved in the beneficial effect of steroids may have an important impact in treatment of arthritis and other inflammatory diseases. If annexin-1 functionally acts as steroids, the reduction or discontinuation of steroid use will be possible.Read moreRead less
Activated Platelets As Unique Targets For Early Imaging And Site-directed Therapy Of Cardiovascular And Inflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$846,979.00
Summary
Heart attack and inflammatory diseases such as rheumatoid arthritis und multiple sclerosis either kill or severely disable people. We use the presence of platelets early on in these diseases to develop methods for early diagnosis as well as potential drugs for site-directed therapy. We have developed new biotechnological tools to perform novel high sensitivity imaging in Positron Emission Tomography (PET) and laser light imaging as well as a localised anti-inflammatory therapy.
During injury or infection, our body’s immune system protects us by launching inflammation. But uncontrolled inflammation drives common diseases such as cancer, diabetes, Alzheimer’s and Parkinson's. This research program will reveal how the body deactivates inflammasomes – protein complexes at the heart of inflammation and disease – so we can design better drugs for treating patients with inflammation-driven disease.
Designing Novel Apolipoprotein A1 Mimetic Peptides As Drug Treatment For Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$60,016.00
Summary
Cardiovascular disease is the formation of atherosclerotic plaques caused by the imbalance between the amount of cholesterol delivered and removed from the arteries. Apolipoprotein A-1 (ApoA-1) is the main protein of high density lipoprotein (HDL) and removes cholesterol out of cell. In this project we are aimed at designing and testing new drugs (ApoA1-mimetic peptides) which will elicit the same anti-atherogenic properties as apoA-1, as a therapeutic agent for prevention of atherosclerosis.
Developing Anti-Inflammatory Drugs Based On Inhibition Of A Human Enzyme
Funder
National Health and Medical Research Council
Funding Amount
$160,000.00
Summary
Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachid ....Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachidonate, PAF, prostaglandins, leukotrienes, etc. there is a consensus that blockade of phospholipid metabolism would represent a major advance on NSAIDs as antiinflammatory agents. No sPLA2-IIa inhibitor is available yet in man. We aim to create an attractive data package showing proof of concept for a potent new type of antiinflammatory drug. This data will give us an improved negotiating position in our commercialisation of a new drug with potential multi-billion dollar markets as diverse as arthritis, asthma, reperfusion injury, organ transplantation and many other currently intractable human ailmentsRead moreRead less
Resolvin E1 Is A Novel Anti-inflammatory And Anti-fibrotic Lipid Mediator For The Treatment Of Chronic Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$519,246.00
Summary
This project will ascertain whether a naturally occurring compound, Resolvin E1 with potent anti-inflammatory properties, can effectively halt the progression of experimental kidney disease. We will also test whether Resolvin E1 can exert other potential benefits in suppressing progressive fibrosis of the kidney. The outcome of this study will allow us to evaluate the therapeutical potential of Resolvin E1 for the treatment of acute and chronic kidney diseases.
The Mechanism Of Action Of Secreted Phospholipase A2 And Its Inhibition In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$554,400.00
Summary
Secretory phospholipase A2 (sPLA2) is an important mediator of inflammation and is clinically associated with the onset and severity of several immune-mediated diseases including arthritis, asthma, atherosclerosis, psoriasis and recently prostate cancer. These are complex diseases which are poorly understood. We have shown that sPLA2 can by itself and in combination with inflammatory cytokines modulate signalling pathways in cells derived from the joints of patients with arthritis to upregulate ....Secretory phospholipase A2 (sPLA2) is an important mediator of inflammation and is clinically associated with the onset and severity of several immune-mediated diseases including arthritis, asthma, atherosclerosis, psoriasis and recently prostate cancer. These are complex diseases which are poorly understood. We have shown that sPLA2 can by itself and in combination with inflammatory cytokines modulate signalling pathways in cells derived from the joints of patients with arthritis to upregulate inflammatory molecules. How this happens is completely unknown. We plan to work out how this enzyme does this. We have also developed small cyclic peptide inhibitors of sPLA2 which potently block the function of the enzyme in these cells. We plan to determine how this happens and if these inhibitors are effective at blocking inflammation and arthritis. The proposal may identify new mechanisms by which secreted factors upregulate inflammation in human cells and may lead to the discovery of new ways to intervene to block these pathways.Read moreRead less
Therapeutic Potential Of Hookworm Secreted Molecules For The Treatment Of Human Autoimmune Diseases
Funder
National Health and Medical Research Council
Funding Amount
$93,597.00
Summary
In developed countries, the increased incidence of allergic and autoimmune diseases has been related to the decreased prevalence of parasitic infections. The present research will explore the role that parasite molecules play in mechanisms that regulate the immune response of their vertebrate hosts and test their potential to become novel therapeutics for the treatment of inflammatory diseases.