Characterisation Of PAR2 Knockout And Transgenic Mice: Towards Gene Therapy For Epithelia Based Inflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$486,943.00
Summary
Debilitating and sometimes fatal diseases like asthma and rheumatoid arthritis urgently require new approaches for their effective management and hopefully, cure. We have recently discovered that the airways posses a powerful and naturally-occuring protective mechanism which is regulated by unique molecules in the membranes of the lining cells of the air passages. These molecules are called protease-activated receptors, or PARs, and are also found on cells lining the inner surfaces of blood vess ....Debilitating and sometimes fatal diseases like asthma and rheumatoid arthritis urgently require new approaches for their effective management and hopefully, cure. We have recently discovered that the airways posses a powerful and naturally-occuring protective mechanism which is regulated by unique molecules in the membranes of the lining cells of the air passages. These molecules are called protease-activated receptors, or PARs, and are also found on cells lining the inner surfaces of blood vessels and joints as well as in skin. We are fortunate to have strains of mice - a species in which the PAR-mediated protective mechanism is well developed - in which the gene for the most important of the PARs found in the lung, PAR2, is missing. These animals are called PAR2 'knock-outs'. We also have another strain of mouse in which the human PAR2 gene has been inserted back into PAR2 knock-out mice. These animals will allow us to determine the importance of PAR2 in protection against asthma, arthritis, vascular disease and deficiencies in skin healing, as well as how PAR2 might be a more effective protective agent in mice rather than humans. Thus, modification of the human gene to make the protective system work as effectively as in the mouse might provide an effective therapy or cure for diseases of the lungs, joints and skin as well as in vascular diseases.Read moreRead less
Defining the antiviral effects of Wolbachia in Aedes aegypti mosquitoes. Mosquitoes that carry a bacterium called Wolbachia do not transmit human pathogenic viruses. These mosquitoes are being developed as a biocontrol tool to prevent mosquito-borne diseases. This project aims to define the molecular basis for virus inhibition by Wolbachia. Using unique biological tools including mosquitoes carrying different strains of Wolbachia that do or do not inhibit dengue virus, the project will define ho ....Defining the antiviral effects of Wolbachia in Aedes aegypti mosquitoes. Mosquitoes that carry a bacterium called Wolbachia do not transmit human pathogenic viruses. These mosquitoes are being developed as a biocontrol tool to prevent mosquito-borne diseases. This project aims to define the molecular basis for virus inhibition by Wolbachia. Using unique biological tools including mosquitoes carrying different strains of Wolbachia that do or do not inhibit dengue virus, the project will define how Wolbachia modifies its host to create an antiviral state. The findings will provide insight into how viral pathogens can be suppressed in insect hosts. This may guide future viral disease intervention strategies for diverse areas afflicted by insect-borne viral disease, including human health and agriculture.Read moreRead less
Transgenic Expression Of The EWS-WT1 Fusion Protein,inducing The Development Of Tumour That Replicates The Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$112,976.00
Summary
A genetic translocation encoding the EWS-WT1 fusion protein is found desmoplastic small round cell tumours. Our aim is to examine the effect of this protein in inducing tumour growth in tissue cell lines. A virus will then be used to introduce the genetic translocation into mice to examine the effect of this protein on tumour growth in a mammal, thereby serving as a 'solid tumour model' to try and identify therapeutic targets.
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
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