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
Three-dimensional solar-energy-driven hydrogen generation from ammonia. This project aims to address the challenges of hydrogen generation, transportation and storage by conceptualising a novel three-dimensional, solar-driven system for ammonia splitting on ultralight catalyst materials. The project expects to generate new knowledge in the area of advanced materials enabled hydrogen technologies through interdisciplinary approaches involving materials science, novel catalysis, and nanotechnology ....Three-dimensional solar-energy-driven hydrogen generation from ammonia. This project aims to address the challenges of hydrogen generation, transportation and storage by conceptualising a novel three-dimensional, solar-driven system for ammonia splitting on ultralight catalyst materials. The project expects to generate new knowledge in the area of advanced materials enabled hydrogen technologies through interdisciplinary approaches involving materials science, novel catalysis, and nanotechnology. Expected outcomes include new catalyst materials, design strategies, and advanced ammonia splitting technologies. This should provide significant benefits, such as newly created knowledge, technological innovation, research training, contributing to hydrogen economy and net zero for a greener environment.Read moreRead less
Development of Dry Coated Pigment Particles: Durability and Dispersion. Tiwest is the only business in the world that mines, separates, refines and manufactures titanium dioxide products in one region. Tiwest has a major impact on the Western Australian economy with more than 700 full time and contract jobs, export earnings of $400M (in 2004) and regular incomes for an estimated 500 businesses. The current wet pigment particle coating process, to ensure ease of handling and longevity, is a major ....Development of Dry Coated Pigment Particles: Durability and Dispersion. Tiwest is the only business in the world that mines, separates, refines and manufactures titanium dioxide products in one region. Tiwest has a major impact on the Western Australian economy with more than 700 full time and contract jobs, export earnings of $400M (in 2004) and regular incomes for an estimated 500 businesses. The current wet pigment particle coating process, to ensure ease of handling and longevity, is a major cost. An optimised pigment dry-coating process would ensure Tiwest's competitiveness through reduced processing costs and improved performance. This development has the potential to increase Tiwest's profitability by 10%.Read moreRead less
Reduction of risk in exploration for petroleum liquids. Australia has an urgent need to establish additional reserves of crude oil. A feature of petroleum exploration in recent decades has been discovery of vast reserves of natural gas but an inability to replace our diminishing reserves of crude oil. Clearly new technology is required to enhance our capability to recognise crude oil-prone rather than gas-prone source rocks. The proposed project will establish the fundamental geochemical pro ....Reduction of risk in exploration for petroleum liquids. Australia has an urgent need to establish additional reserves of crude oil. A feature of petroleum exploration in recent decades has been discovery of vast reserves of natural gas but an inability to replace our diminishing reserves of crude oil. Clearly new technology is required to enhance our capability to recognise crude oil-prone rather than gas-prone source rocks. The proposed project will establish the fundamental geochemical processes that will support the potential exploration techniques, developed with Woodside Energy Limited support.Read moreRead less
Dementia Associated To Diabetes: Prevention Through The Modulation Of Cerebrovascular Integrity
Funder
National Health and Medical Research Council
Funding Amount
$719,770.00
Summary
Diabetic insulin resistance is reported to induce cognitive decline and dementia. An accumulating body of evidence suggest that compromised integrity of neurovascular unit and following changes in cerebral lipid homeostasis may be centrally involved in the neurodegeneration and cognitive deficits. Therefore, the project aims to prevent the insulin resistance-associated cognitive impairment by modulating the integrity of cerebrovasculature and lipid homeostasis.
Guarding and evolving the genome: interactions between DNA-repair enzymes and damaged DNA. The application of structural biology techniques to the area of DNA repair allows us to understand the full implications linking genes and proteins to the molecular mechanisms of diseases such as cancer and hereditory conditions. Studies in this highly internationally competitive area are already established in the Bond laboratory, which has recently relocated to Australia. The use of forward-thinking stru ....Guarding and evolving the genome: interactions between DNA-repair enzymes and damaged DNA. The application of structural biology techniques to the area of DNA repair allows us to understand the full implications linking genes and proteins to the molecular mechanisms of diseases such as cancer and hereditory conditions. Studies in this highly internationally competitive area are already established in the Bond laboratory, which has recently relocated to Australia. The use of forward-thinking structural biology approaches to solve difficult technical problems will foster collaborations within Australia and with leading laboratories abroad, providing excellent up-to-date research training for students and postdoctoral researchers.
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Aboriginal And Non-Aboriginal Women Perpetrators Of Violence: A Trial Of A Prison-based Intervention (Beyond Violence)
Funder
National Health and Medical Research Council
Funding Amount
$1,411,825.00
Summary
The proposed study will be the first of its kind in Australia to test a violence prevention program (Beyond Violence) targeting mental health, substance use and violence among incarcerated female offenders with a history of violence. This research responds to the rapidly escalating imprisonment rates among Aboriginal and non-Aboriginal women (particularly for violent offences), and focuses intervention efforts on improving well-being and decreasing reoffending among this vulnerable group.
Discovery Early Career Researcher Award - Grant ID: DE230100978
Funder
Australian Research Council
Funding Amount
$406,818.00
Summary
A new Iron Age! Making Iron complexes fit for C-C cross-coupling catalysis. This project aims to develop new iron catalysts as alternatives to the expensive and increasingly rare noble metals currently used in C-C bond forming reactions, the most important single-step in the fine-chemicals sector.
This project expects to create a flexible yet robust framework by introducing a hemilabile ligand into the backbone of the iron complex to control the number of vacant coordination sites.
Expected outc ....A new Iron Age! Making Iron complexes fit for C-C cross-coupling catalysis. This project aims to develop new iron catalysts as alternatives to the expensive and increasingly rare noble metals currently used in C-C bond forming reactions, the most important single-step in the fine-chemicals sector.
This project expects to create a flexible yet robust framework by introducing a hemilabile ligand into the backbone of the iron complex to control the number of vacant coordination sites.
Expected outcomes of this project are 1) iron complexes able to catalyse biaryl couplings from sustainable substrates and 2) knowledge on structure-property relationships of iron-based catalytic processes.
Australia will benefit by applying its own resources and help preserving the valuable noble metals for processes relying on them.Read moreRead less