Altered Gp130-mediated Signalling In The Regulation Of Pulmonary Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$373,956.00
Summary
Pulmonary fibrosis is a chronic diffuse interstitial lung disease often of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation using anti- inflammatory dru ....Pulmonary fibrosis is a chronic diffuse interstitial lung disease often of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation using anti- inflammatory drugs, almost exclusively steroids. The effectiveness of steroids is variable although generally poor and can be associated with significant side effects suggesting that other approaches need to be considered. Data generated over the past decade also have established the concept that the molecular processes underlying the development of fibrosis may represent a new opportunity for therapeutic intervention. This project will build on previous studies examining the effects of a family of molecules called cytokines that signal through gp130 as critical determinants of disease susceptibility and progression. gp 130 is a shared component in the receptor complexes for IL-6 family cytokines and can signal down two major pathways. We have shown that the development of lung fibrosis depends on which specific signalling pathway is used. This study will determine how fibrosis is controlled by these pathways. Our data raises the possibility of developing pharmacological manipulators of gp130 signalling pathways that would suppress fibrosis but leave normal cellular defense mechanisms necessary for host defense in the lung intact.Read moreRead less
Validation Of Stat3 As A Therapeutic Target In Diseases Arising From Its Inappropriate Activation By Gp130 Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$674,142.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the exte ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.Read moreRead less
Novel Pathomechanisms And Therapeutic Approaches In Alzheimer's Disease And Related Dementias
Funder
National Health and Medical Research Council
Funding Amount
$804,106.00
Summary
Currently, over 200,000 Australians are affected by Alzheimer's disease (AD) or frontotemporal lobar degeneration (FTLD), causing a huge socio-economic damage. To overcome the lack of effective treatments, we need to understand the underlying causes and translate them into therapy. Using state-of-the-art cell culture and genetic mouse models, I will reveal fundamental processes in AD and related dementias, and develop tailored treatments to battle these devastating disorders.
Chronic Bacterial Infection And The Generation Of T Cell Memory: Implication For Vaccination Against Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Two million people die from tuberculosis (TB) each year. The immune system is unable to eradicate the TB bacterium, and the type of immune response needed to protect against the disease is poorly understood. We will use animal models of TB infection and sophisticated immunological techniques to decipher how the TB bacterium interacts with the immune sytem and causes disease. We will also develop new TB vaccines that aim to boost the immune response in the lung, the main site of TB infection.
Many people with organ failure need a transplant to survive. Unfortunately most patients who would benefit from a transplant are unable to receive one because of the shortage of living or deceased donors. A possible solution to this shortage is to use animal organs. Pigs are the most suitable animal donor. This project aims to produce and test genetically modified pigs which can provide organs that will be resistant to rejection when transplanted into human recipients.
Manipulating Immunity To Mycobacterium Tuberculosis With Novel Vaccines And Immunotherapeutics
Funder
National Health and Medical Research Council
Funding Amount
$524,770.00
Summary
Tuberculosis (TB) is an enormous world health problem with 2 million deaths per year and an estimated one third of the world s population infected with the TB bacterium. People who become infected with the bacterium and cannot clear the infection are at great risk of developing TB later in life. Control of TB is confronted with two major problems. First, the only vaccine available for TB, known as BCG, is not very effective at preventing the disease. We do not know why BCG is not an effective va ....Tuberculosis (TB) is an enormous world health problem with 2 million deaths per year and an estimated one third of the world s population infected with the TB bacterium. People who become infected with the bacterium and cannot clear the infection are at great risk of developing TB later in life. Control of TB is confronted with two major problems. First, the only vaccine available for TB, known as BCG, is not very effective at preventing the disease. We do not know why BCG is not an effective vaccine and the type of immune response required to achieve optimal protection against TB is not fully understood. Second, the drugs currently used to treat TB are expensive, treatment times are long and drug resistance is increasing at an alarming rate. Therefore there is an urgent need to develop new vaccines and therapies against TB. We propose to use animal models of TB infection and sophisticated immunological techniques to compare immune responses generated by TB, BCG and new generation vaccines developed in our laboratory. This will allow us to identify the key features of a vaccine that results in effective, long-lasting protection against TB infection. Novel strategies to increase the immune response in the lung, the main site of TB infection, will also be examined. This will involve pulmonary delivery of molecules that increase the number and effectiveness of lung antigen presenting cells, which are necessary to drive the right type of immune response to eradicate the TB bacterium. Increasing lung immunity will be used to either boost the effect of the BCG vaccine, or as a therapy to kill the bacterium in those already infected. This is an internationally competitive project and our team is at the forefront of this research effort. The development of new vaccines to prevent TB or new strategies to treat established TB infection would be a major medical breakthrough and a represent a significant achievement for Australian health and medical research.Read moreRead less
Type 2 diabetes is caused by multiple genetic defects, resulting in high blood sugar levels. These high sugar levels are primarily due to a decrease in the concentration of insulin, a hormone produced by the pancreas. A number of recent studies have aimed to identify which genes are regulated under conditions that mimic diabetes. One gene shown to have altered expression levels under these conditions is an enzyme called fructose-1,6-bisphosphatase (or FBPase). This enzyme is involved in the meta ....Type 2 diabetes is caused by multiple genetic defects, resulting in high blood sugar levels. These high sugar levels are primarily due to a decrease in the concentration of insulin, a hormone produced by the pancreas. A number of recent studies have aimed to identify which genes are regulated under conditions that mimic diabetes. One gene shown to have altered expression levels under these conditions is an enzyme called fructose-1,6-bisphosphatase (or FBPase). This enzyme is involved in the metabolism of sugar and is usually expressed at undetectable levels in the pancreas, but when blood sugar levels are high, the amount of FBPase in the pancreas increases considerably. We hypothesise that this increase in FBPase may contribute to the decrease in insulin secretion by the pancreas, seen in the diabetic state. The aim of this proposal therefore is to study mice that we have modified to express increased FBPase specifically in the pancreas, in order to determine whether this will lead to a decrease in insulin release and to diabetes. If this is the case, then FBPase could be targeted for the development of drugs that would improve the control of blood sugar levels in diabetes.Read moreRead less
Evaluation Of Pharmacological Therapies For Friedreich Ataxia Using Cellular And Mouse Models
Funder
National Health and Medical Research Council
Funding Amount
$589,425.00
Summary
Friedreich ataxia (FRDA) is an inherited disorder of the nervous system and muscles. The genetic defect that causes FRDA results in reduced levels of an essential protein termed frataxin. By using information and resources generated as part of the Human Genome Project we have developed new techniques to study human gene expression in cellular and animal systems. Our aim is to identify and develop new pharmacological approaches for the restoration of FRDA gene expression and the therapy of FRDA.
Functional Integration Of Transplanted Neural Stem Cells In Huntingtons Disease
Funder
National Health and Medical Research Council
Funding Amount
$373,360.00
Summary
The proposed study investigates important questions related to restoration of brain functions in a neurodegenerative disease, Huntington's disease, using neural stem cells (precursors of nerve cells). It will expand our understanding of the mechanisms underlying the development of Huntington's disease, and provide insights into potential therapeutic use of neural stem cells for the currently incurable Huntington's disease.
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