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
Smoking Cessation For Youth Project Booster And Cohort Tracking Study
Funder
National Health and Medical Research Council
Funding Amount
$135,550.00
Summary
Adolescence is a critical period for the establishment of adult drug use behaviours. If smoking does not commence in teenage years it is unlikely to occur. This innovative project not only continues to address tobacco control with this important age group but also builds on evidence from a randomised intervention trial involving over 4,000 Year 9 students tracked over two years. This project was called the Smoking Cessation for Youth Project (SCYP). Preliminary longitudinal analyses of the SCYP ....Adolescence is a critical period for the establishment of adult drug use behaviours. If smoking does not commence in teenage years it is unlikely to occur. This innovative project not only continues to address tobacco control with this important age group but also builds on evidence from a randomised intervention trial involving over 4,000 Year 9 students tracked over two years. This project was called the Smoking Cessation for Youth Project (SCYP). Preliminary longitudinal analyses of the SCYP data indicate that the intervention students were significantly less likely to smoke heavily (smoking five or more days per week) than the control group and that intervention students were also significantly less likely to have tried smoking than the control group. These results represent a world first in evidence that population-based smoking cessation interventions among teenagers can be successful. The proposed project will determine the extent to which these positive intervention effects are sustainable, two years post intervention, as our cohort moves into Year 12. In addition to tracking the possible decay of SCYP intervention effects, the proposed project will also measure the effects of a booster intervention delivered students when they are in Year 12 (2002). The Year 12 intervention will comprise an innovative self-help 'magazine style' booster and a supportive environmental intervention involving school nurses and local GPs. This proposal represents a cost-effective opportunity to measure the effectiveness of a Year 12 tobacco cessation booster intervention. Further data on tobacco smoking behaviour in 2002 will also enable us to determine how long the SCYP intervention appears to affect behaviour and whether 'boosters' are needed in later secondary school years to maintain the benefits.Read moreRead less