Role Of Transition Metal Ions And Redox Activity In The Development Of Atherosclerotic Plaques
Funder
National Health and Medical Research Council
Funding Amount
$196,018.00
Summary
Metal ions such as iron and copper have been reproted to be present in the lesions present in diseased human arteries and it has been suggested that these metal ions contribute to the development of atherosclerosis (hardening of the arteries) via their ability to catalyse the formation of highly reactive molecualr fragments called free radicals. Though metal ions are known to catalyse such reactions in test-tube experiments, both the presence of metal ions in diseased arteries and their ability ....Metal ions such as iron and copper have been reproted to be present in the lesions present in diseased human arteries and it has been suggested that these metal ions contribute to the development of atherosclerosis (hardening of the arteries) via their ability to catalyse the formation of highly reactive molecualr fragments called free radicals. Though metal ions are known to catalyse such reactions in test-tube experiments, both the presence of metal ions in diseased arteries and their ability to generate free radicals is controversial. This study will employ a novel, minimally-invasive, technique to assess the nature and quantity of metal ions present in well-defined human and animal lesions at different stages of lesion development. The ability of these metal ions to catalyse free radical formation from components present in the artery wall will also be assessed. The release of these metal ions from the artery wall to added organic molecules will be assessed as this might minimise their potential to cause damage, and provide a possible therapeutic strategy. These studies will therefore provide valuable information as to the significance and role of reactive metal ions in the development of human artery disease and the possible prevention, or minimisation, of such processes.Read moreRead less
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$606,000.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that c ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that cause severe damage. Further, cells deficient in frataxin are sensitive to oxidant stress and Fe chelators rescue oxidant-mediated death of cells from FA patients. Indeed, free radical scavengers have shown to be of use in the treatment of this disease. Studies in DR's lab during this NHMRC grant have shown that frataxin is down-regulated by erythroid differentiation or the haem precursor, protoporphyrin IX (BLOOD 2002;99:3813-22). These data indicate a role for frataxin in Fe metabolism and the pathogenesis of FA. In this study we will continue to examine the role of frataxin in the way cells handle Fe using experimental models developed under the current NHMRC grant. These include transfected cell lines with low frataxin expression generated using an expression vector containing anti-sense frataxin cDNA. Further we obtained the frataxin conditional KO mouse and generated a breeding colony. These animals display many of the pathological features of FA and are the best current model of the disease. Indeed, they will be critical for assessing the role of frataxin in Fe metabolism and as a model to test the ability of Fe-binding drugs to prevent the pathology observed. We designed lipid-soluble chelators that can enter the mitochondrion to bind Fe (Biochim Biophys Acta 2001;1536:133-140) and these ligands will be tested to prevent disease progression in the KO mice. This exciting research is crucial for understanding the pathogenesis of FA and in creating new therapies.Read moreRead less
Biosynthetic Hooks for an Enigmatic Marine Toxin. This project aims to characterise the genetic basis for the production of tetrodotoxin; a potent neurotoxin of ecological and biomedical significance. We hypothesise that tetrodotoxin is produced by microorganisms and transferred via the food web to fish, molluscs and other marine animals. Our integrated genomic and synthetic biology approach, targeting key biosynthesis genes, will reveal pathways for the production of tetrodotoxin and other pote ....Biosynthetic Hooks for an Enigmatic Marine Toxin. This project aims to characterise the genetic basis for the production of tetrodotoxin; a potent neurotoxin of ecological and biomedical significance. We hypothesise that tetrodotoxin is produced by microorganisms and transferred via the food web to fish, molluscs and other marine animals. Our integrated genomic and synthetic biology approach, targeting key biosynthesis genes, will reveal pathways for the production of tetrodotoxin and other potentially valuable compounds. In addition to providing unprecedented insight into the ecology and biosynthesis of this enigmatic toxin, the data generated will enable improved management of seafood safety and provide a foundation for the future development of novel neuroactive compounds.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100170
Funder
Australian Research Council
Funding Amount
$580,000.00
Summary
Bioaffinity mass spectrometry infrastructure to identify small molecules binding to therapeutic targets. The development of anti-infective therapies is challenging because the underlying biology and biochemistry of pathogen virulence is not yet completely understood. This mass spectrometer facility will be used to identify small molecules suited for development into new therapies for malaria, tuberculosis and HIV.
Mid-Career Industry Fellowships - Grant ID: IM230100154
Funder
Australian Research Council
Funding Amount
$1,049,904.00
Summary
Fungi Power: Designer Fungal Cell Factories for Advanced Biomanufacturing. This project aims to build an advanced biomanufacturing platform based on filamentous fungi in collaboration with industry. Using synthetic biology, the project expects to engineer superior fungal host strains customisable to the needs of the industry and to address their technological gaps. The expected outcomes include the development of cost-efficient and sustainable fungal-based bioprocesses for the companies to produ ....Fungi Power: Designer Fungal Cell Factories for Advanced Biomanufacturing. This project aims to build an advanced biomanufacturing platform based on filamentous fungi in collaboration with industry. Using synthetic biology, the project expects to engineer superior fungal host strains customisable to the needs of the industry and to address their technological gaps. The expected outcomes include the development of cost-efficient and sustainable fungal-based bioprocesses for the companies to produce products, such as fine chemicals, pharmaceutical actives and food ingredients. The project would provide significant benefits by enabling existing and emerging companies' commercial successes and competitiveness in global markets, creating new jobs and resulting in the growth of the bio-economy in Australia.Read moreRead less
Engineered Hydroxamic Acids for Zirconium-89 Positron Emission Tomography (PET) Imaging of Prostate Cancer. Positron emission tomography (PET) using a zirconium-89-ligand complex bound to a prostate-specific membrane antigen is used to detect and monitor prostate cancer. The hydroxamic acid-based ligand bound to zirconium has a high affinity towards iron, which can cause metal exchange in vivo and loss of radiotracer. The project will prepare new ligands with a higher specificity towards zirconi ....Engineered Hydroxamic Acids for Zirconium-89 Positron Emission Tomography (PET) Imaging of Prostate Cancer. Positron emission tomography (PET) using a zirconium-89-ligand complex bound to a prostate-specific membrane antigen is used to detect and monitor prostate cancer. The hydroxamic acid-based ligand bound to zirconium has a high affinity towards iron, which can cause metal exchange in vivo and loss of radiotracer. The project will prepare new ligands with a higher specificity towards zirconium over iron, and measure immuno-PET imaging activity. A second series of macrocyclic zirconium-specific ligands will be prepared to establish the relationship between variable water-lipid solubility and pharmacokinetic properties. The results will increase the capability of immuno-PET for prostate cancer detection and improve survival outcomes.Read moreRead less
Diene regenerative Diels-Alder reactions to access chemical scaffolds. This project aims to develop methods and strategies that allow rapid access to biologically active chemical scaffolds based on natural products. Natural products and their analogues are vital starting points for drug discovery as they provide unique chemical diversity. Without efficient methods for their production, it is not possible to exploit this diversity. This project will develop an efficient, modular strategy that wil ....Diene regenerative Diels-Alder reactions to access chemical scaffolds. This project aims to develop methods and strategies that allow rapid access to biologically active chemical scaffolds based on natural products. Natural products and their analogues are vital starting points for drug discovery as they provide unique chemical diversity. Without efficient methods for their production, it is not possible to exploit this diversity. This project will develop an efficient, modular strategy that will allow the preparation of a wide range of chemicals in a timely manner. Restoring access to potent biologically active materials is expected to generate chemical probes and lead to molecules that could have biomedical value.Read moreRead less
Industrial Transformation Training Centres - Grant ID: IC230100046
Funder
Australian Research Council
Funding Amount
$5,000,000.00
Summary
ARC Training Centre for Radiochemical Technologies and Precision Radiopharmaceuticals. This project aims to train the next generation of radiochemists and discover new molecular approaches to harness radioactivity. Novel chemistry exploiting molecular incorporation of radioactive elements, stable chelation of metal radionuclides, bioconjugation methodologies, radioactivity capture via nanomaterials and cages, and the design of new peptidomimetic targeting molecules will deliver technological adv ....ARC Training Centre for Radiochemical Technologies and Precision Radiopharmaceuticals. This project aims to train the next generation of radiochemists and discover new molecular approaches to harness radioactivity. Novel chemistry exploiting molecular incorporation of radioactive elements, stable chelation of metal radionuclides, bioconjugation methodologies, radioactivity capture via nanomaterials and cages, and the design of new peptidomimetic targeting molecules will deliver technological advances to radiopharmaceutical science. Outcomes will include a highly-skilled workforce and enhanced commercial capacity to meet a rapidly escalating global radiopharmaceutical market. This project will provide significant benefits by securing an internal supply chain and know-how for cutting-edge radiochemical technologies.Read moreRead less