To Biochemically Trick P-Glycoprotein (Pgp) To Target Resistance Via Lysosomal Pgp
Funder
National Health and Medical Research Council
Funding Amount
$603,848.00
Summary
We have discovered an innovative biochemical strategy whereby our novel compounds exploit and trick a part of the detoxification machinery, that is the transporter, P-glycoprotein, to specifically kill drug resistant cancer cells. Herein, we take advantage of this biochemical mechanism to design novel and safe drugs to selectively target resistant tumours.
Is Placental Aging The Key To Understanding, Predicting And Preventing Stillbirth?
Funder
National Health and Medical Research Council
Funding Amount
$473,861.00
Summary
Stillbirth occurs in 35 times as many pregnancies as sudden infant death but the causes are unknown. This project will help to develop tests that can predict the risk of stillbirth so that the obstetrician can deliver the baby before it dies. The investigators hypothesise that stillbirth is due to aging of the placenta and that markers of the aging placenta can be detected in the mother’s blood. The project brings together experts in the placenta, aging and obstetric care of high risk pregnancy.
The Role Of Presenilin In Metal Homeostasis And Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$86,335.00
Summary
Presenilin, a protein involved in Alzheimer’s disease (AD), may regulate copper and zinc levels. Copper and zinc are essential nutrients however a deficiency or excess can cause disease. Promising metal-altering AD drugs, are in various stages of clinical trial. I aim to characterize the interaction of Presenilin and metals using both mouse and cultured human cell models that are deficient in Presenilin. Understanding this interaction should lead to better drug design and treatment of AD.
The Efficacy Of N-acetyl Cysteine As An Adjunctive Treatment For First Episode Psychosis
Funder
National Health and Medical Research Council
Funding Amount
$2,143,069.00
Summary
First episode psychosis may foreshadow devastating, chronic illness. Psychosis follows a staged, progressive pathway. There is evidence to suggest illness progression can be diminished and perhaps even averted if appropriate treatments are given at the early stages of illness. This project will test if N-acetycysteine (NAC) administered to young people who have experienced a first episode of psychosis can help prevent this early psychotic experience from developing into a chronic disorder.
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.
Many heart diseases are associated with impairment of energetics of the heart. Improving the heart's energetics can lead to improved survival and long-term outcomes. Perhexiline is a heart medication that works by improving the way the heart uses energy. Although effective, it is associated with long-term toxicities. Better understanding of this medication may lead to less adverse effects and also provide a basis for further investigation of drug development in the future.
Assessment Of Oxidant Stress And Mitochondrial Dysfunction In Young Adults With Iron Loading Diseases
Funder
National Health and Medical Research Council
Funding Amount
$601,979.00
Summary
Disorders of iron metabolism are particularly prevalent in Australia and the consequences of excess iron can be severe. Liver disease is frequently associated with iron loading. The commonest form of iron loading can be treated readily, but it is unclear when the first signs of tissue damage occur and thus at what stage treatment should commence. This project will examine in detail the relationship between body iron levels and signs of tissue damage in young subjects with iron loading disease.
Targeting Oxidant-dependent Pathways To Improve Stroke Outcomes In COPD
Funder
National Health and Medical Research Council
Funding Amount
$1,069,574.00
Summary
Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4th largest cause of death worldwide. Patients with COPD are at increased risk for stroke and this is even higher in the weeks following a lung viral infection. The reason for this is unknown so the aim of this study is to determine why people with COPD are at increased risk for stroke and then develop novel treatments to prevent or reduce stroke in COPD patients.
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