Phenotypic Studies Of The NaSi-1 Transporter Knock-out Mouse
Funder
National Health and Medical Research Council
Funding Amount
$268,264.00
Summary
Sulfate is an essential nutrient for cell growth and survival. Despite this, sulfate levels are rarely measured clinically and very little is known about the consequences of disturbed blood sulfate levels.The human kidneys regulate sulfate levels in the body, by mechanisms that are not fully characterised. Our laboratory has isolated a gene (Nas1) from humans and mice, which encodes a protein involved in sulfate absorption from the diet. Nas1 also controls sulfate excretion into the urine, by re ....Sulfate is an essential nutrient for cell growth and survival. Despite this, sulfate levels are rarely measured clinically and very little is known about the consequences of disturbed blood sulfate levels.The human kidneys regulate sulfate levels in the body, by mechanisms that are not fully characterised. Our laboratory has isolated a gene (Nas1) from humans and mice, which encodes a protein involved in sulfate absorption from the diet. Nas1 also controls sulfate excretion into the urine, by regulating kidney reabsorption. Normally, very little sulfate is lost in the urine. However, individuals with autism, Alzheimers, Parkinsons, motor neurone disease and liver cirrhosis, have been reported to have reduced blood sulfate levels. The mechanisms underlying the low blood sulfate levels in these disorders, have not been characterised. Recently, we generated a mouse lacking the Nas1 gene. This mouse has very low blood sulfate levels and suffers from growth retardation, reduced fertility and displays seizures. In this study, we plan to investigate these phenomena in the Nas1 knock out mouse and determine the role of low blood sulfate levels on these conditions. We also plan to characterise the role of low blood sulfate levels on the expression of genes in various body organs, using a gene array approach. In addition, we plan to study wound repair and the detoxification process in our Nas1 knock out mouse, which we expect to be affected due to low blood sulfate levels. These studies will establish the roles sulfate plays in mammalian physiology and will provide a foundation for studying diseases that are associated with changes in blood sulfate levels.Read moreRead less
Elucidation Of Trafficking Of The Menkes (MNK;ATP7A) Copper-transporting ATPase In Epthelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic free radicals. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and mad cow disease. Menkes disease is an inherited and usually lethal copper ....Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic free radicals. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and mad cow disease. Menkes disease is an inherited and usually lethal copper deficiency disorder in humans, and the diverse and detrimental symptoms of this disease related to organs and tissues described above is a stark indicator of the essentiality of copper. We have carried out extensive research on Menkes disease and in particular the Menkes protein which in normal individuals plays a major role in maintaining the copper balance in cells, i.e. enough copper to satisfy nutritional needs of cells but not too much which causes toxicity. The normal Menkes protein catalyses the transport of copper across membranes of cells to the areas where it is needed by copper-dependent enzymes and is essential for copper absorption into the body from the gut. The normal Menkes protein functions as a molecular pump. We have discovered that this protein can sense copper concentrations in the cell and when these reach potentially toxic levels it can move (traffic) via small vesicles to the plasma membrane which surrounds cells. There it pumps the excess copper out of the cell and returns to its original location. Our studies are directed to understanding the molecular mechanisms which permit this remarkable protein to achieve a copper balance in living cells. The findings will be of major significance in understanding and treating acquired and inherited diseases involving copper deficiency or copper toxicity including osteoporosis, cardiovascular disease, and Alzheimer's disease.Read moreRead less
Functional Characterisation Of Pendrin: The Anion Transporter Causing Pendred Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Mutations in the human pendrin protein cause progressive hearing loss from an early age in Pendred syndrome. Using techniques of molecular and cellular biology, we intend to test the effects of Pendred-causing mutations on the function of pendrin expressed in frog and cultured mammalian cells. Our approach will enable us to determine how pendrin functions in both the normal and diseased states, which is currently unknown. This will allow us to consider ways of correcting the ion channel defect a ....Mutations in the human pendrin protein cause progressive hearing loss from an early age in Pendred syndrome. Using techniques of molecular and cellular biology, we intend to test the effects of Pendred-causing mutations on the function of pendrin expressed in frog and cultured mammalian cells. Our approach will enable us to determine how pendrin functions in both the normal and diseased states, which is currently unknown. This will allow us to consider ways of correcting the ion channel defect associated with the Pendred syndrome.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
Chloroquine Resistance And The Physiology Of The Malaria Parasite S Digestive Vacuole
Funder
National Health and Medical Research Council
Funding Amount
$287,921.00
Summary
Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms ....Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms. Chloroquine was, for many years, the mainstay of antimalarial chemotherapy and was, in many senses, a 'wonder-drug' cheap, safe and effective. However the emergence and spread of parasites that are resistant to chloroquine has meant that the drug is now largely useless as an antimalarial. Chloroquine kills (sensitive) parasite through an effect on the parasite s digestive vacuole an internal acidic compartment in which the parasite breaks down protein taken up from its host red blood cell. This compartment plays a crucial role in the growth and proliferation of the parasite. Yet we understand very little about its basic physiology, and nor do we understand the mechanism by which chloroquine-resistant parasites are able to survive exposure to the drug. The aim of the work proposed here is to gain an increased understanding of some of the mechanisms underlying the physiology of the parasite s digestive vacuole, as well as some of the factors influencing the accumulation of chloroquine within this compartment. The former part of the work may well reveal new antimalarial drug targets. The latter part of the work will increase our understanding of the mechanism of chloroquine resistance, thereby laying the groundwork for strategies by which these mechanisms might be circumvented and chloroquine-related drugs thereby restored to the front-line of our ongoing and increasingly desperate fight against malaria.Read moreRead less