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
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.
Hypothalamic Signalling In Cortical And Trabecular Bone Anabolic Activity
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
Osteoporosis is a disease associated with an exponential rise in the number of fractures in the elderly. These fractures are so common that around 1 in 3 women and 1in four men will be affected. They cause pain, disability that can be permanent disability and are associated with premature death. Current treatments are able to effectively increase bone strength in osteoporotic patients but can not return bone strength to normal. Some new treatments can restore bone strength to some extent but the ....Osteoporosis is a disease associated with an exponential rise in the number of fractures in the elderly. These fractures are so common that around 1 in 3 women and 1in four men will be affected. They cause pain, disability that can be permanent disability and are associated with premature death. Current treatments are able to effectively increase bone strength in osteoporotic patients but can not return bone strength to normal. Some new treatments can restore bone strength to some extent but these are limited by expense and safety concerns. We have discovered a pathway in the brain that reduces bone formation and by blocking this pathway we can achieve doubling of the amount of bone in key bone sites. This occurs due to a marked increase in the amount of new bone formed. In fact, genetic manipulation of this pathway was able to double the speed at which bone is made by the skeleton. Excitingly, these increases in bone were possible in adult mice, suggesting such changes could be potential therapy for human patients. However, in order to be able to harness this pathway we must understand what molecules within the brain are responsible for the signals that reach the bone. Our proposal aims to identify the nerve signalling molecule(s) and the receptor for these signals within the brain that initiates the increase in bone formation. This project ultimately aims to identify a target for new therapies that could cause this beneficial effect by administration of a simple treatment, preferably by mouth in adult humans.Read moreRead less
Understanding The Genetic Determinants Of Central Corneal Thickness And Its Functional Role In Glaucoma Pathophysiology
Funder
National Health and Medical Research Council
Funding Amount
$297,263.00
Summary
Glaucoma is a common cause of blindness and visual diability in Australia. It is caused by a combination of environmental and genetic factors. People with a thin cornea (the clear covering at the front of the eye) are at increased risk of glaucoma. We are investigating the biological link between the cornea and glaucoma as well as identifying genes that determine corneal thickness. Some of these genes may also cause glaucoma. Understanding this will lead to better diagnosis and treatment.
The Role Of Tissue Factor In The Regulation Of Extracellular Matrix Remodelling And Angiogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$241,980.00
Summary
The aim of the project is to understand how some blood clotting factors may be involved with the regulation of the extracellullar matrix (the material that exists between cells) and angiogenesis (new blood vessel formation). New blood vessel growth occurs in a wide variety of situations including: healing of a flesh wound, the healing phase following a heart attack, development of the eye disease associated with sugar diabetes, in and around a cancerous growth, in the uterus during the normal me ....The aim of the project is to understand how some blood clotting factors may be involved with the regulation of the extracellullar matrix (the material that exists between cells) and angiogenesis (new blood vessel formation). New blood vessel growth occurs in a wide variety of situations including: healing of a flesh wound, the healing phase following a heart attack, development of the eye disease associated with sugar diabetes, in and around a cancerous growth, in the uterus during the normal menstrual cycle, and for the normal growth and development of the placenta and a new baby. The processes by which these new blood vessels form and the factors contributing to the maintenance of their structure are incompletely understood. However, it is known that the interaction of cells and the surrounding extracellular matrix is critical for normal cell function and in particular for new blood vessel formation. Studies in this project will seek to define a relationship between some of the factors which regulate blood clotting, and those that regulate turnover of the extracellular matrix and new blood vessel formation. In particular, how blood clotting factors may be invovled in the regulation of the extracellular matrix will be studied in a rapidly developing tissue, the mouse placenta. The role of blood clotting factors in regulation of new blood vessel formation into an artificial avascular tissue will also be examined. These studies will employ some of the new genetic techniques to understand new roles for proteins which have been traditionally thought to act in only one way. This research has the potential to provide new insights into how blood vessels are formed and are subsequently maintained. This increased understanding will provide the knowledge required for the development of new therapeutic strategies to correct the process when it goes wrong, is unwanted or underdeveloped in human disease.Read moreRead less
Investigation Of Dysfunction Of SIGMAR1 In Transgenic Mouse Models, A Novel Gene Implicated In Neurodegeneration
Funder
National Health and Medical Research Council
Funding Amount
$492,119.00
Summary
At present, there are no effective therapies for frontotemporal dementia or motor neuron disease. We have identified the SIGMAR1 gene as having a crucial role for these diseases. More importantly, there are therapeutically relevant small molecule drugs that are known to modulate the activity of this gene. We aim to determine the efficacy of pharmacological modulation of Sigma-1 receptor activity in mouse models of dementia.
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
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
Novel Immune Evasion Strategy Of CMV: Targeting Of An Adhesion Molecule Involved In Leukocyte Recruitment/activation.
Funder
National Health and Medical Research Council
Funding Amount
$391,650.00
Summary
Herpesviruses cause persistent lifelong infection. To achieve this they have evolved a variety of mechanisms to evade the immune response mounted to combat them. They also minimise the expression of their gene products to a minimal suite of latency associated proteins. One member of the herpesvirus family is cytomegalovirus. While in healthy individuals it causes aymptomatic infection, it causes significant disease and mortality in individuals whose immune systems are suppressed such as transpla ....Herpesviruses cause persistent lifelong infection. To achieve this they have evolved a variety of mechanisms to evade the immune response mounted to combat them. They also minimise the expression of their gene products to a minimal suite of latency associated proteins. One member of the herpesvirus family is cytomegalovirus. While in healthy individuals it causes aymptomatic infection, it causes significant disease and mortality in individuals whose immune systems are suppressed such as transplant and AIDS patients, and also in the fetus which has a poorly developed immune system. Cytomegaloviruses set up persistent and latent lifelong infections. In the current proposal we will be assessing a viral gene present in mouse cytomegalovirus that codes for a protein that binds to a cellular adhesion molecule. This adhesion molecule called CD44 is involved in the migration of immune effector cell to sites of infection and in their activation. The viral gene thus represents a potential immune evasion molecule with the ability to subvert the host's immune response by reducing the infiltration and-or activation of cells that clear virus infection. The results from these studies could help us design anti-viral drugs that interfere with the effect of this viral protein, thus providing a novel anti-viral treatment strategy.Read moreRead less