Upscaling Cardiac Tissue Engineering: Differentiation Of IPS Cells, Enrichment And Bionic Approaches
Funder
National Health and Medical Research Council
Funding Amount
$709,758.00
Summary
Stem cell therapies to repair heart muscle are experimental methods which promise future clinical treatments. Our tissue engineering chamber model provides a protective environment for implanted cells and generates contracting heart tissue. Towards clinical application we will scale up the tissue volume produced by: improving cell supply with new stem cell technologies, design chambers for bulk cell implantation, adopt a bionic approach to cell pacing and apply the model into larger animals.
We aim to grow body tissues for surgery, including heart muscle, liver and pancreatic islets (for diabetes) and will investigate using stem cells to repair the brain after stroke. We will attempt to boost the expansion of blood vessels in growing tissues using molecular tools we have found crucial for cell signaling. In growing heart tissues and in stroke we will improve drugs that might boost the potential of stem cells to regenerate damaged tissues
Pharmacological Strategy For Blocking Lung Cell Damage By Toxic Smoke Constituents.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
People retrieved from burning buildings or other hazardous situations involving fires are often at risk of death due to the effects of inhaled smoke. This reflects the presence of some very toxic substances in smoke that are products of the combustion of wood, vegetation and synthetic building materials. The most toxic substance present within smoke is acrolein, a very reactive chemical that attacks cells in the lining of the lung. This can result in a life-threatening condition known as oedema, ....People retrieved from burning buildings or other hazardous situations involving fires are often at risk of death due to the effects of inhaled smoke. This reflects the presence of some very toxic substances in smoke that are products of the combustion of wood, vegetation and synthetic building materials. The most toxic substance present within smoke is acrolein, a very reactive chemical that attacks cells in the lining of the lung. This can result in a life-threatening condition known as oedema, where the lung is flooded with fluids and is unable to perform its respiratory function. At present, the clinical approaches used to treat smoke inhalation victims are mostly directed against offsetting the symptoms of lung injury and do not take into account the role of lung cell injury by toxic substances in smoke such as acrolein. This project will provide a better understanding of the chemical events underlying the injury caused by smoke to lung cells, and also into possible drug strategies for treating victims of smoke inhalation. The work will explore the ability of a range of compounds that are chemically related to a blood pressure-lowering medicine (hydralazine) to protect lung cells against such smoke-induced damage. The work will employ a range of modern research techniques to understand the events occurring in lung cells exposed to smoke. Once this is understood, these approaches will be used to test the various drug compounds for their abilities to prevent the death of cells exposed to smoke or its toxic constutuent acrolein. This work will yield new information on a series of compounds concerning their ability to block the toxicity of smoke to lung cells. The goal is to identify one or two molecules that can be carried forward to testing in smoke-exposed animals.Read moreRead less
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
Novel Omega-3 Fatty Acid Epoxides And The Activation Of Cellular Survival Pathways
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Recent studies have reported that foods and oils containing high levels of omega-3 fatty acids have beneficial effects in patients with arthritis and cardiovascular disease. The mechanisms by which these dietary changes produce health benefits are unclear but it is known that omega-3 fatty acids can replace omega-6 and other fatty acids in cells; these omega-6 acids are more common in western diets. A number of enzymes in cells convert fatty acids to oxygenated derivatives and some of these have ....Recent studies have reported that foods and oils containing high levels of omega-3 fatty acids have beneficial effects in patients with arthritis and cardiovascular disease. The mechanisms by which these dietary changes produce health benefits are unclear but it is known that omega-3 fatty acids can replace omega-6 and other fatty acids in cells; these omega-6 acids are more common in western diets. A number of enzymes in cells convert fatty acids to oxygenated derivatives and some of these have potent protective effects that allow cells to survive in the presence of toxic stimuli. We have found that epoxides formed from the omega-3 fatty acid stearidonic acid are extremely potent protective agents in cells - more so that epoxides from omega-6 acids like arachidonic acid. The present project seeks to identify omega-3 fatty acid epoxides with potent and long-lived beneficial effects in cells, relate these properties to those of omega-6 fatty acid epoxides and then understand how the omega-3 epoxides enhance cell survival. The findings will provide a rational basis from which to understand the beneficial effects of dietary modification already seen in clinical studies. By understanding the biochemical and molecular events in cells that are activated by omega-3 fatty acid epoxides we may be able to design therapies, most likely involving changes in dietary fat intake, that could benefit individuals with arthritic, cardiovascular and other conditions. Given the high incidence of these conditions in this country the potential impact of the findings from this project could be highly significant and are consistent with the national research priority healthy ageing.Read moreRead less
Functional Interplay Of Transcriptional Activators In The Regulation Of The Cytoprotective Human CYP2J2 Gene
Funder
National Health and Medical Research Council
Funding Amount
$480,828.00
Summary
Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have ....Human cytochrome P450 2J2 (CYP2J2) is expressed in many tissues. This enzyme acts on polyunsaturated fatty acids to form epoxides that control ion fluxes, the size of blood vessels and inflammation, and also help cells to survive the damaging effects of oxygen deprivation and other stresses. So CYP2J2 has an important role in both normal and injured cells. Increasing the amount of CYP2J2 in cells may be extremely valuable in the defence against injury. Until recently, however, no treatments have been able to do this but we now know that the biologically important vitamin A derivative all-trans-retinoic acid (ATRA) can increase CYP2J2 in cells. In this project we will build on this novel finding to develop treatments that increase CYP2J2 in tissues. About 10% of people have a variant CYP2J2 gene that differs from the common form by one nucleotide. This polymorphic variant can decrease the amount of the CYP2J2 enzyme and increase cardiovascular risk. We ve found that this polymorphism is located in a critical control region of the gene and affects how the gene responds to transcription factors. The present project will study in detail the regulation of the CYP2J2 gene and its naturally occurring variant by transcription factors that bind to this control region. We will also test how the polymorphic version of the gene responds to stress stimuli and to treatments like ATRA that increase the amount of the wild-type gene in cells. Studying human gene regulation is difficult because we cannot easily measure their levels in individuals. So we will make transgenic mice to study human CYP2J2 regulation and will test whether the treatments we devise in cells also work in vivo. These studies will help us to design pharmacological strategies to increase CYP2J2 in cells. By maintaining the beneficial effects of CYP2J2, and understanding how these are altered in the variant, a significant outcome of the project could be a new treatment of cardiovascular disease.Read moreRead less