How Important Is Collagen Destruction In Arthritis? A Study With Collagenase-resistant Knockin Mice
Funder
National Health and Medical Research Council
Funding Amount
$529,723.00
Summary
Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is n ....Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes collagen damage in explant culture, however it is not known whether inhibiting aggrecanases is sufficient to block cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after damage to the collagen scaffold. These studies propose that clipping of the collagen scaffold may initiate aggrecan release; with progressive degeneration and collagen clipping, more aggrecan is lost, until ultimately the scaffold is severely damaged and aggrecan is severely depleted. Cartilage can only withstand a limited degree of collagen degradation and any significant damage to the network is widely considered to be irreparable. It is unclear what role aggrecanases and collagenases have in initiating and perpetuating cartilage damage. We have mice with aggrecan resistant to aggrecanases and mice with inactive aggrecanase. We will also create mice with collagen resistant to collagenase. We will use these mice to determine the contribution of collagenases and aggrecanases to the initiation and progression of cartilage damage, in three models of joint disease. We will identify differences in time of disease onset, rate of disease progression and disease severity. The results will show whether one or both activities is important for the initiation and progression of joint disease. This will reveal whether single or combination therapies are required for the management of arthritis. The research will inform the pharmaceutical industry on directions for the development of new drugs to prevent joint disease.Read moreRead less
Functional Analysis Of Recently Identified Novel Glaucoma Genes.
Funder
National Health and Medical Research Council
Funding Amount
$519,918.00
Summary
Glaucoma is the commonest cause of irreversible blindness in the world. Recently, through genetic studies in cohorts of blinding glaucoma cases from Australia, our group has found that variants in two genes increase the risk of blinding glaucoma. This project will investigate how these genes contribute to pathological changes in the optic nerve and retina, at the back of the eye, that lead to glaucoma. This knowledge will be useful for developing new strategies to treat glaucoma.
This proposal aims to examine how the oral bacterial pathogen, P.gingivalis, interacts with the host to worsen the severity of disease in rheumatoid arthritis. We propose a new mechanism whereby the pathogen directly activates a major destructive host pathway to promote tissue and bone destruction, which are two of the clinical hallmarks of rheumatoid arthritis. We also propose that this host-pathogen interaction occurs in periodontal disease.
Neuroprotection Against Parkinson’s Disease With Remote Photobiomodulation
Funder
National Health and Medical Research Council
Funding Amount
$314,818.00
Summary
Treating the head of rodents with low-intensity 670nm light protects against Parkinson’s disease (PD), but the large size of the human skull and brain precludes clinical translation of this treatment. We have discovered that the brain is also protected when light is targeted at peripheral tissues (e.g. a limb), overcoming problems of delivery. This project aims to optimise this treatment and better understand how it works, to lay the scientific basis for a clinical trial.
Mast Cell Proteases Suppress Respiratory Viral Infections And Alleric Inflammation Of The Airways
Funder
National Health and Medical Research Council
Funding Amount
$665,532.00
Summary
Severe RSV infection and asthma accounts for poor quality of life in our community and current treatments have limited effects. Although the factors regulating these disorders are poorly understood, mast cells (MCs) may play important roles. We have shown MC protease-6 protects against viral infection. Here we will identify how MC and their factors are involved in the control of severe respiratory infections and allergic disease of the lung, and identify potential new ways to treat these conditi ....Severe RSV infection and asthma accounts for poor quality of life in our community and current treatments have limited effects. Although the factors regulating these disorders are poorly understood, mast cells (MCs) may play important roles. We have shown MC protease-6 protects against viral infection. Here we will identify how MC and their factors are involved in the control of severe respiratory infections and allergic disease of the lung, and identify potential new ways to treat these conditions.Read moreRead less
The Effect Of Metals On Neurofibrillary Tangle Formation
Funder
National Health and Medical Research Council
Funding Amount
$333,313.00
Summary
The majority of studies into Alzheimer's disease (AD) have focussed on two brain lesions- the plaque and neurofibrillary tangle (NFT), which are believed to have a causative role in AD. Our lab has made several seminal discoveries about the role that metals play in the development of plaques. We are now extending this work to evaluate the role of metals in NFT formation. These studies will provide insight into the formation and possible treatments for this primary brain lesion in AD.
Development Of A Preventive Strategy For Rheumatic Heart Disease Using An Experimental Model
Funder
National Health and Medical Research Council
Funding Amount
$370,846.00
Summary
Based on animal studies, we aim to demonstrate that the worsening of heart damage seen in patients with rheumatic heart disease (RHD) is due to repeated infections with bacteria (group A streptococci: GAS). The heart damage is caused by continual immune damage to the heart and valves and this has adverse effects on heart function. We will also investigate a novel way to prevent the development of RHD.
Targeting MicroRNA (miRNA) As A Unified Therapeutic Approach To The Treatment Of Asthma And Allergic Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$675,030.00
Summary
Approximately 30% of our community suffers from allergic inflammation (asthma/rhinitis/dermatitis) that results in poor quality of life. The factors regulating these disorders are poorly understood and current treatments only target the symptoms and not the cause of disease. MicroRNA control gene expression and are emerging as potential regulators of inflammation. This project will identify the role of microRNA in the regulation of allergic diseases and their potential as new therapeutic targets ....Approximately 30% of our community suffers from allergic inflammation (asthma/rhinitis/dermatitis) that results in poor quality of life. The factors regulating these disorders are poorly understood and current treatments only target the symptoms and not the cause of disease. MicroRNA control gene expression and are emerging as potential regulators of inflammation. This project will identify the role of microRNA in the regulation of allergic diseases and their potential as new therapeutic targets.Read moreRead less