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.
Using cutting edge sequencing and genotyping technology, genes causing common and rare human diseases will be identified, and genetic methods developed to diagnose genetic diseases in both antenatal and postnatal life. Treatments for common rheumatic diseases affecting tens of thousands of Australians will be developed informed by these genetic findings.
Glucocorticoids (or 'steroids') are among the most commonly used drugs in the world, chiefly used for inflammatory diseases. However, they have major predictable side effects that have been known for over 60 years. Science has, til now, failed to deliver an alternative that delivers the effects of steroids without the side effects. This application is for funds to support the development of the discovery of the protein known as GILZ towards a treatment to help patients.
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.
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.
Functional Effects Of Antibodies To Collagen On Cartilage Synthesis And Degradation
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
It has been shown that antibodies to collagen type II in cartilage occur in ~70% of patients with early rheumatoid arthritis, suggesting that autoimmunity to cartilage collagen may play a part in the devleopment of this destructive arthritis. An animal model widely used as a model of human RA is the disease collagen induced arthritis (CIA). It is induced by immunisation of mice with collagen II; antibodies to collagen II are critical for the development of CIA. However not all such antibodies ar ....It has been shown that antibodies to collagen type II in cartilage occur in ~70% of patients with early rheumatoid arthritis, suggesting that autoimmunity to cartilage collagen may play a part in the devleopment of this destructive arthritis. An animal model widely used as a model of human RA is the disease collagen induced arthritis (CIA). It is induced by immunisation of mice with collagen II; antibodies to collagen II are critical for the development of CIA. However not all such antibodies are disease-associated. There may be particular regions on the collagen molecule where antibody-binding causes damage. This project is based on the hypothesis that antibodies to collagen type II, which transfer arthritis in mice, are those that react specifically with regions of the collagen fibrils that are crucial for cartilage stability and function. We plan to test this hypothesis in an in vitro system using cultured cartilage. We predict, based on our preliminary data, that antibodies to collagen II from mice with CIA will interfere with the normal assembly and structure of cartilage. We will test this by adding antibodies under precisely defined conditions to cultured cartilage, and analysing the matrix that is synthesised. The study would then be extended to RA with a comparison of the regions of collagen II that react with antibodies of mouse and human origin. Showing that antibodies to collagen II are directly destructive, allowing for an understanding of their site and mode of action, would greatly advance our understanding of the cause of RA and would lead to more effective forms of treatment.Read moreRead less