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Development And Pre-clinical Evaluation Of G-DSF Inhibitors For Inflammatory Joint Disease
Funder
National Health and Medical Research Council
Funding Amount
$88,329.00
Summary
G-CSF was originally identified as a cytokine regulating the production of neutrophils and haemopoietic stem cells from the bone marrow and it is currently used clinically for these properties in bone marrow transplant patients around the world. Anti-cytokine therapy with TNF blockade has recently been introduced for the treatment of rheumatoid arthritis. However, not all patients respond to TNF inhibition. We have gathered extensive data which shows that G-CSF also promotes inflammation in expe ....G-CSF was originally identified as a cytokine regulating the production of neutrophils and haemopoietic stem cells from the bone marrow and it is currently used clinically for these properties in bone marrow transplant patients around the world. Anti-cytokine therapy with TNF blockade has recently been introduced for the treatment of rheumatoid arthritis. However, not all patients respond to TNF inhibition. We have gathered extensive data which shows that G-CSF also promotes inflammation in experimental models of inflammatory joint disease. We propose to develop inhibitors of G-CSF as a novel form of anti-cytokine therapy for inflammatory joint disorders, such as rheumatoid arthritis.Read moreRead less
Targeting Autophagy As A Means Of Control Of Cytokine Production In SLE
Funder
National Health and Medical Research Council
Funding Amount
$616,518.00
Summary
Systemic lupus erythematosus (SLE, or lupus) is a common immune disease that causes organ damage and loss of life, chiefly affecting young women. There is no cure for SLE. We have discovered that a natural process called 'autophagy' could be a way to limit inflammation during SLE. In this project we will discover whether this could lead to a new way to treat this disease.
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
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
Pathogen Sensing In Autoinflammatory And Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$340,724.00
Summary
Mammals have evolved an array of mechanisms to sense microbes. These immune sentinels must distinguish self from non-self to activate an immune response. The initiation, amplification and quenching of an immune response is a carefully orchestrated process that eliminates invading pathogens while minimising collateral damage to host tissues. This research focuses on proteins that restrict immune responses to prevent inflammatory diseases such as rheumatoid arthritis and psoriasis.