Copper is an essential trace element with the potential for toxicity. Copper deficiency can be fatal to developing animals due to the multiple organ abnormalities caused by the reduced activity of important copper containing enzymes. Dietary copper deficiency can cause iron unresponsive anaemia in children and may contribute to heart disease and connective tissue defects in adults. A variant form of a copper containing protein is thought to contribute to Alzheimer's disease and the affected prot ....Copper is an essential trace element with the potential for toxicity. Copper deficiency can be fatal to developing animals due to the multiple organ abnormalities caused by the reduced activity of important copper containing enzymes. Dietary copper deficiency can cause iron unresponsive anaemia in children and may contribute to heart disease and connective tissue defects in adults. A variant form of a copper containing protein is thought to contribute to Alzheimer's disease and the affected protein in mad cow disease may normally play a role in copper biology of the brain. Given the importance of copper for normal health and the potential for toxicity, the levels of copper in the body are tightly regulated. There are two main sites for this regulation: the uptake of dietary copper across the intestine and the excretion of excess copper into the bile. This proposal addresses the molecular control of copper uptake in the intestine. Much of our understanding about the regulation of the uptake of copper from dietary sources was obtained prior to the era of modern molecular biology. Prof. Mercer's laboratory has recently made significant discoveries into the molecular basis of copper metabolism in human cells. Based on these findings and finding of others about copper metabolism in yeast, we have proposed a model incorporating these newly described molecules to explain how the body might regulate the uptake of copper in the intestine. We propose to investigate this model using cell culture models of the intestine and in mouse models. These studies will extend our knowledge of copper biology and may provide insight for potential treatments of copper related disorders.Read moreRead less
Identification Of Cardiac Sarcoplasmic Reticulum Targets For Cardiotoxic Drugs
Funder
National Health and Medical Research Council
Funding Amount
$265,986.00
Summary
Anthracyclines are drugs which are used successfully in chemotherapy. Unfortunately, these drugs can lead to serious heart problems which sometimes result in death, and the mechanisms behind this remain elusive. Finding the specific targets of these drugs and how these drugs affect heart contraction may lead to designing drug cocktails which protect the heart from side effects.
Effects Of Ageing On Hepatic Drug Clearance And Mechanisms Of Drug Induced Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
With increasing age, there is increase in disease, for which medications may provide benefit, and an increase in the risk of adverse drug reactions, even after considering the increase in medication use by older people. We will investigate how the liver clears drugs from the blood in old age. This will guide dosing of medications for older people. We will also study how drugs injure the liver in old age and test interventions to prevent this toxicity.
Copper Pathways Are Altered In Parkinson’s Disease: Implications For Cell Vulnerability
Funder
National Health and Medical Research Council
Funding Amount
$341,398.00
Summary
The cause of brain cell death in Parkinson’s disease is unknown but we have shown that copper levels are reduced in the vulnerable brain regions in this disorder. As copper is vital for the normal function of key brain proteins we suggest that reduced copper contributes to cell damage in vulnerable brain regions. This project investigates why brain copper levels are reduced in the Parkinson’s disease brain and the consequences of this change for brain cell function and survival.
SULT4A1 is not a sulfotransferase, but a sulfotransferase inhibitor. It forms high affinity heterodimers with other sulfotransferases via a conserved dimerisation site in its carboxyl terminus attenuating catalytic activity. Consequently, it is important for the metabolism of numerous important molecules including estrogens, thyroid hormones, neurotransmitters and many therapeutic agents.
Pesonalised Risk Prediction For Severe Treatment-related Gastrointestinal Toxicity In Paediatric Cancer Patients Using Pre-treatment Gut Microbiome Analysis
Funder
National Health and Medical Research Council
Funding Amount
$408,768.00
Summary
The gut is home to trillions of good and bad bacteria, critical to human health. Each person has a different balance of bacteria, unique to their gut, which shapes their immune system and susceptibility to disease. I will investigate how the unique gut bacteria, in children with blood cancer, can be used to predict which children will develop severe gut side effects (diarrhoea) from their chemotherapy. This will identify high-risk children, enable personalised treatment and improve survival.
Radiotherapy Treatment For Prostate Cancer - A Change In Practice Based On Direct Evidence For Targeting And Toxicity Effects Using Real Outcomes Data
Funder
National Health and Medical Research Council
Funding Amount
$555,129.00
Summary
Radiotherapy for prostate cancer treatment will be more effective when we have better knowledge of what patient anatomy needs to be targeted, and what needs to be avoided. This project will combine data collected during a large Australasian prostate cancer radiotherapy trial, ‘RADAR’, with data collected using new patient imaging methods to determine how patient anatomy impacts on the effectiveness of their treatment and the side-effects they experience.
Development Of Therapeutic Copper Delivery Agents For Menkes Disease
Funder
National Health and Medical Research Council
Funding Amount
$651,467.00
Summary
Menkes disease does not currently have an effective treatment. The disease is caused by genetic defects that reduce copper transport into the brain and cause mental retardation and death. We have developed drugs that deliver copper into the brain and should cure Menkes disease. We aim to demonstrate that our drugs are effective in mice that have the same genetic defect as patients. Successful results will allow us to begin treating Menkes disease patients to determine if we can cure the disease.
Evaluation Of The Safety Of Lead Compounds For Allergic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$310,568.00
Summary
Asthma is one of the most common chronic respiratory diseases in developed countries and is typically treated with corticosteroids which provide symptomatic relief and coarse non-specific treatment of the underlying disease. We are pursuing innovative therapies by targeting a different enzyme, HPGD2S, involved in the inflammatory mechanisms of asthma. We have developed potent, anti-inflammatory drug candidates and aim to profile the safety of these compounds before entering clinical studies.