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
Molecular And Cellular Studies Of The Copper-transporting ATPases Affected In Menkes And Wilson Diseases
Funder
National Health and Medical Research Council
Funding Amount
$558,300.00
Summary
Copper is an element that is essential for life but is highly toxic in excess. Because of this, the regulation of copper uptake, distribution in the body and excretion of excess is a very tightly regulated process. Until recently little was known about the molecular basis of this process. Two genetic disorders that show these two aspects of copper are Menkes disease (deficiency) and Wilson disease (toxicity). Both diseases are caused by mutations in similar copper pumping proteins. Our research ....Copper is an element that is essential for life but is highly toxic in excess. Because of this, the regulation of copper uptake, distribution in the body and excretion of excess is a very tightly regulated process. Until recently little was known about the molecular basis of this process. Two genetic disorders that show these two aspects of copper are Menkes disease (deficiency) and Wilson disease (toxicity). Both diseases are caused by mutations in similar copper pumping proteins. Our research is trying to establish the molecular mechanisms used in the body to control copper metabolism. We made a major breakthrough in 1993 with the isolation of the gene affected in Menkes disease, and we continue to be one of the leading groups in the world in studying the molecular mechanisms that handle copper, and the importance of these mechanisms in health and disease. Research into the biology of copper has become much more important following the recent discoveries of the involvement of the metal in such important neurodegenerative conditions such as Alzheimer's, Mad Cow, and Parkinson's diseases. Health effects from the lack of copper may be widespread also, copper deficiency is suspected to contribute to some common diseases, such as cardiovascular problems and osteoporosis. Our research is providing information about copper transport mechanisms that are necessary for the understanding of, and may lead to better treatment and diagnosis of common and important diseases. In this grant we propose to continue our studies into the molecular signals that control the copper pumps, that make the regulation of copper metabolism possible. We also will use various test systems for studying the effect of mutations on the activity of these proteins and relate these effects to the type of disease produced in patients.Read moreRead less
Ion Transport In The Human Malaria Parasite, Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Malaria is responsible for hundreds of millions of cases and an estimated 1.5-2.7 million deaths each year. The disease is caused by a microscopic parasite which is becoming increasingly resistant to antimalarial drugs. There is a very real possibility that there will soon be parts of the world in which malaria is an untreatable disease, and there is an urgent need to identify new drug targets. However, despite the significance of the malaria parasite for world health, the basic physiology of th ....Malaria is responsible for hundreds of millions of cases and an estimated 1.5-2.7 million deaths each year. The disease is caused by a microscopic parasite which is becoming increasingly resistant to antimalarial drugs. There is a very real possibility that there will soon be parts of the world in which malaria is an untreatable disease, and there is an urgent need to identify new drug targets. However, despite the significance of the malaria parasite for world health, the basic physiology of this organism is poorly understood. This project focuses on the mechanisms involved in ion balance in the parasite. Ion balance is a basic 'housekeeping' function in all cells, and disruption of the mechanisms involved will inevitably impair cell function. The work proposed here will lead to an understanding of ion balance in the intracellular parasite and provide insight into whether the mechanisms involved may be suitable antimalarial drug targets.Read moreRead less
Neural Mechanisms Mediating Inhibitory Influences Of Hyperthermia, Fever And Age On Water Intake
Funder
National Health and Medical Research Council
Funding Amount
$324,125.00
Summary
An adequate intake of fluid following losses of body water that can occur as the result of sweating in hot weather, exercise, vomiting or diarrhoea is necessary so that dangerous levels of dehydration do not occur. Thus, it is important for our health that thirst is properly stimulated when we do become dehydrated, in order that we are aware that we must drink water. There may be conditions in which the thirst mechanism is inhibited, and the aim of these experiments is to identify and understand ....An adequate intake of fluid following losses of body water that can occur as the result of sweating in hot weather, exercise, vomiting or diarrhoea is necessary so that dangerous levels of dehydration do not occur. Thus, it is important for our health that thirst is properly stimulated when we do become dehydrated, in order that we are aware that we must drink water. There may be conditions in which the thirst mechanism is inhibited, and the aim of these experiments is to identify and understand mechanisms by which the thirst mechanism in the brain is supressed. We have observed that a high body temperature may have an inhibitory influence on thirst in rats, and it is also known that thirst mechanisms are depressed in elderly people. If we can identify the regions of the brain that are involved and the mechanisms underpinning this reduced thirst, then it will be possible to identify and alert people at risk and to design strategies to prevent dangerous levels of dehydration occurring due to reduced thirst, particularly in the elderly. This may also apply to to people who may be working or undertaking vigorous exercise in hot weather or taking certain medications.Read moreRead less
Type 2 diabetes causes significant health problems. The fundamental reasons underlying this disease are not fully known and will require molecular analysis of proteins critical to blood glucose control. This work aims to define a novel pathway that responds to circulating nutrients. The research will enhance our understanding of the links between diet and metabolic disease, with potential to reveal much needed therapeutic targets and/or dietary interventions for the treatment of Type 2 diabetes.
Protein Networks Mediating Copper Balance And Their Break-down In Disease.
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Neurological disorders (eg. Alzheimer s, Parkinson s and prion diseases) impose a growing health burden on society. Exciting new therapeutic possibilities stem from the discovery that copper (Cu) plays a central role in the disease process. Our research will help foster a holistic understanding of the protein network regulating copper balance, particularly in the brain, and where it breaks down in disease. Clinical benefits include new targets for diagnosis and treatment of Cu-related diseases.
The Role Of Perlecan In Tensional Connective Tissues
Funder
National Health and Medical Research Council
Funding Amount
$605,037.00
Summary
Musculoskeletal diseases affect tension and weight bearing connective tissues which have notoriously poor repair capabilities. These conditions are difficult to treat clinically and surgical repair in many cases does not provide a return to optimal joint function impinging on the quality of life of afflicted individuals and their carers. Our project aims to better understand the structure and function of these tissues in health and disease with a view to improving repair strategies.