Defining The Role Of GILZ In Inflammatory Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$675,030.00
Summary
Corticosteroids are commonly used to treat inflammatory diseases such as arthritis. Their action is based on effects on natural inflammation control pathways. One such pathway is that mediated by the protein known as GILZ (glucocorticoid induced leucine zipper). The function of this protein in disease is not well understood, and the research proposed here will increase understanding of its role. This knowledge could yield new treatments for arthritis and other inflammatory diseases.
Polyunsaturated Fatty Acids Mimetics With Anti-inflammatory Properties
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Autoimmune diseases are responsible for a high incidence of morbidity and mortality in our community. Immunosuppressive drugs-anti-inflammatory agents have played important roles in treatment of these diseases as well as in helping to prevent rejection of transplanted tissues-organs. There is an ongoing search by the medical community for better immunosuppressive drugs and agents for use for these purposes. Based on studies conducted in the last few years, we have partially identified structural ....Autoimmune diseases are responsible for a high incidence of morbidity and mortality in our community. Immunosuppressive drugs-anti-inflammatory agents have played important roles in treatment of these diseases as well as in helping to prevent rejection of transplanted tissues-organs. There is an ongoing search by the medical community for better immunosuppressive drugs and agents for use for these purposes. Based on studies conducted in the last few years, we have partially identified structural elements on polyunsatrated fatty acids (PUFA) which are responsible for specific biological functions. Using this information, we have synthesized a large panel of previously unavailable PUFA which we can use to target T lymphocytes and drive the biological activity of these compounds, preferentially towards immunosuppression. By conducting the research outlined in this project, we are likely to either identify a lead immunosuppressive compound or generate new information for further synthesis of PUFA-based compounds for further examination as potential immunosuppressive agents.Read moreRead less
The Role Of Post-translationally Modified Antigen In Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$609,535.00
Summary
Rheumatoid arthritis (RA) is an inflammatory disease of joints. People who get RA often develop antibodies which react against proteins found in inflamed joints. We will investigate why cells of the immune system react against these proteins in RA, and identify which joint proteins, especially abnormal proteins, are targeted. This will allow us to design new approaches to treat RA in a way that just targets the response to these abnormal proteins, rather than the entire immune system.
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.
Induction Of Antigen-specific Tolerance Through Inhibition Of RelB Function In Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$421,980.00
Summary
This proposal builds on preliminary data showing the possibility that responses of the immune system to antigens can be suppressed by modifying cells known as dendritic cells using an inhibitory drug. The drug appears to be able to control the ability of dendritic cells to educate the immune system about antigens. When antigens presented continuously are harmful to the immune system, they produce diseases such as rheumatoid arthritis and allergies. The experiments to be undertaken specifically l ....This proposal builds on preliminary data showing the possibility that responses of the immune system to antigens can be suppressed by modifying cells known as dendritic cells using an inhibitory drug. The drug appears to be able to control the ability of dendritic cells to educate the immune system about antigens. When antigens presented continuously are harmful to the immune system, they produce diseases such as rheumatoid arthritis and allergies. The experiments to be undertaken specifically look at means to prevent and reverse diseases like rheumatoid arthritis through the use of dendritic cells.Read moreRead less
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
ADAMTS-5 Activity And The Effect Of A Dominant-negative Mutant
Funder
National Health and Medical Research Council
Funding Amount
$540,235.00
Summary
Cartilage loss is a feature of arthritis and is caused by enzymes. We discovered that loss of a critical cartilage component is caused by the enzyme ADAMTS-5. We also discovered that a mutant form of ADAMTS-5 blocks the normal emzyme, possibly by a novel binding interaction. If we can understand how this interaction works, we can exploit it for the design of new arthritis therapies. This project aims to identify the novel interaction and improve out understanding of cartilage destruction.
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