Improving Treatment Strategies For Chronic Alphaviral Arthritic Diseases
Funder
National Health and Medical Research Council
Funding Amount
$643,624.00
Summary
Chikungunya virus and Ross River virus cause epidemics of acute and chronic arthritic disease in humans, which is often poorly managed with current treatments. This grant seeks to understand the mechanisms that give rise to disease in order to identify improved treatment strategies. Both the persistence of viral replication in joint tissues and unnecessary inflammatory responses appear to be important factors driving chronic disease.
MIF Regulation Of MKP-1 And Glucocorticoid Responses In RA
Funder
National Health and Medical Research Council
Funding Amount
$398,156.00
Summary
Rheumatoid arthritis (RA) is a common chronic inflammatory disease which affects 1% of Australians. Up to 70% of patients are treated with 'steroids', which are drugs with major side effects. Recent research has shown that sensitivity to steroids is controlled by a number of natural proteins, and that balance between these proteins controls the effectiveness of steroids. The proposed research will define the interactions between these proteins.
Inhibition Of Interferon-alpah-beta By Chikungunya Virus And The Induction Of Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$709,193.00
Summary
Chikungunya virus is a mosquito borne virus which has caused epidemics of arthritis around the world (recently 260,000 people Reunion Island, France and 1.6 million people in India). The virus is ordinarily very sensitive to the main mammalian anti-viral defence system (interferon alpha-beta). This grant seeks to understand how, despite the activation of this system during infection, the virus manages to persist and cause 3-6 months of debilitating arthritis.
TBK1 Inhibitors As Novel Therapeutics For Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$511,722.00
Summary
A key feature of rheumatoid arthritis is inflammation in affected joints causing pain and immobility. New drugs that selectively block processes that are dysregulated in rheumatoid arthritis are needed to better treat this disease. The protein called TBK1 is a key regulator of inflammation and we aim to develop drugs that inhibit TBK1 activity thereby blocking the inflammation and symptoms associated with rheumatoid arthritis.
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
Identifying A Novel Aggrecanase In Mouse Cartilage
Funder
National Health and Medical Research Council
Funding Amount
$299,227.00
Summary
Destructive enzymes degrade cartilage in arthritis. Aggrecan is a major structural molecule that gives cartilage its cushioning properties, and aggrecan is also destroyed by harmful enzymes in arthritis. We have discovered a new enzyme that degrades aggrecan. This project aims to identify and study this new enzyme, and to determine its role in aggrecan degradation.
Modulation Of Osteoclast Formation And Function To Prevent Joint Destruction In Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$443,250.00
Summary
Rheumatoid arthritis is a disease that affects about 200,000 Australians. It is characterised by painful joint destruction leading to work disability, diminished quality of life and decreased life expectancy. The usual treatment of arthritis leads to less inflammation however it cannot be relied upon to control bone and joint destruction. Patients often have long term worsening of joint function despite short and medium term improvement in joint pain and swelling. One reason for this paradox may ....Rheumatoid arthritis is a disease that affects about 200,000 Australians. It is characterised by painful joint destruction leading to work disability, diminished quality of life and decreased life expectancy. The usual treatment of arthritis leads to less inflammation however it cannot be relied upon to control bone and joint destruction. Patients often have long term worsening of joint function despite short and medium term improvement in joint pain and swelling. One reason for this paradox may be that while research has mainly focused on inflammation, far less is known about the processes responsible for bone damage. Normally, specialised bone cells called osteoclasts carry out bone breakdown during growth and maintenance of the skeleton. In rheumatoid arthritis, these cells are responsible for the joint damage; this proposal, therefore, focuses on inhibiting the activity of these cells as a new therapy. So far, our work using a model of human rheumatoid arthritis has demonstrated that it is possible to separate joint inflammation from joint damage by selectively targeting osteoclasts with an inhibitor known as Osteoprotegerin. Besides Osteoprotegerin, we have identified two novel molecules named OCIL and sFRP-1 and shown that they are present in the joints of animals and humans with arthritis. Very recent experiments in our laboratory show that in the test tube, OCIL and sFRP-1 (like Osteoprotegerin) block osteoclast activity. The sFRP-1 molecule may also block a very important messenger molecule in arthritis called tumour necrosis factor. We therefore propose to study the effect of OCIL and sFRP-1 in the joints of mice with arthritis. We expect that these new inhibitors will have favorable effects on joint damage. If so, they could undergo further testing for use in humans. We believe that investigations along these lines may provide a rationale for an entirely new treatment approach to improve the long term outcome for patients with arthritis.Read moreRead less
The Role Of SOCS-1 And SOCS-3 In Regulating Acute Inflammatory Arthritis.
Funder
National Health and Medical Research Council
Funding Amount
$444,910.00
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease which mainly targets joints. The disease causes chronic joint pain, stiffness and loss of joint mobility, leading to increasing difficulty in carrying out day to day activities. Treatment for RA has gradually improved, but remains inadequate for many patients. Although the cause is unknown, progress has been made in understanding the molecular pathways which drive RA. The disease is characterised by the production of high levels of infl ....Rheumatoid arthritis (RA) is a chronic inflammatory disease which mainly targets joints. The disease causes chronic joint pain, stiffness and loss of joint mobility, leading to increasing difficulty in carrying out day to day activities. Treatment for RA has gradually improved, but remains inadequate for many patients. Although the cause is unknown, progress has been made in understanding the molecular pathways which drive RA. The disease is characterised by the production of high levels of inflammatory mediators called cytokines. This finding has led to the development and introduction of specific cytokine inhibitors into clinical practice, although a significant number of patients fail to respond to treatment. An alternative approach to develop new treatments for RA would be to use the body's natural inhibitors to limit the actions of inflammatory cytokines. One such inhibitor is Suppressor of Cytokine Signalling-1 (SOCS-1). Using animal models, we have shown that mice lacking SOCS-1 develop more severe arthritis and have identified the different cell types it acts on. Further studies are still needed before SOCS-1 can be developed as a treatment for RA. We aim to identify the major cell type responsible for the increased severity of disease seen when SOCS-1 is absent. This will allow for treatment to be targetted to the most appropriate cells in the joint. We also aim to study the related molecule SOCS-3, to see whether it has similar effects on inhibiting the severity of disease. These studies will provide more information on the activity of SOCS proteins during inflammatory diseases in general and RA in particular and and may lead to new approaches for the treatment of RA.Read moreRead less
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.
Towards Selective Targeting Of HDACs For Anti-inflammatory Applications
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
HDAC inhibitors are anti-cancer drugs that kill rapidly growing cells (like cancer cells). These drugs also have anti-inflammatory properties and so may be beneficial in chronic inflammatory diseases such as as Rheumatoid Arthritis. However, it is unknown how they reduce inflammation. In this project we aim to understand how HDAC inhibitors act as anti-inflammatory agents and to design new HDAC inhibitors with reduced side effects for the treatment of inflammatory diseases.