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
$285,990.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin i ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin is down-regulated by either erythroid differentiation or the haem precursor protoporphyrin IX (Becker and Richardson, submitted). These data strongly suggest a role for frataxin in iron metabolism. In the present study we will continue to assess if frataxin plays a role in the way cells handle iron. Using a unique model of mitochondrial iron overload developed in my lab (Richardson et al. (1996) BLOOD 87:3477), we will extensively investigate the iron metabolism of the mitochondrion in order to determine the function of frataxin and its role in Friedreich's ataxia. In addition, we have developed a series of new drugs known as iron chelators that can enter the mitochondrion due to their high lipid solubility (Becker and Richardson 1999 J. Lab. Clin. Med. 134:510). These latter drugs are far more effective than the chelator currently used to treat iron overload, desferrioxamine (DFO). Indeed, our chelators have been designed to result in high iron chelation efficacy but low toxicity (see Becker and Richardson, 1999). This exciting research may be crucial in understanding the development of FA and in creating new therapies such as the use of iron chelators.Read moreRead less
Non-invasive Measurement And Imaging Of Hepatic Iron Concentrations Using Nuclear Magnetic Resonance
Funder
National Health and Medical Research Council
Funding Amount
$341,210.00
Summary
Iron overload diseases such as genetic haemochromatosis and thalassaemia affect up to 0.5% of the world's population. These diseases result in deposition of dangerously high concentrations of iron in tissues of the body. Organs such as the liver and heart are at particular risk of being damaged. In order to manage a patient's condition optimally, a knowledge of their tissue iron concentrations is required. Currently the most direct and reliable way of achieving this is to remove a small sample o ....Iron overload diseases such as genetic haemochromatosis and thalassaemia affect up to 0.5% of the world's population. These diseases result in deposition of dangerously high concentrations of iron in tissues of the body. Organs such as the liver and heart are at particular risk of being damaged. In order to manage a patient's condition optimally, a knowledge of their tissue iron concentrations is required. Currently the most direct and reliable way of achieving this is to remove a small sample of the patient's liver for chemical analysis. Apart from the fact that the procedure is unpleasant and carries some risk, the measurement made by this method has some uncertainty because the liver iron concentration can vary significantly from place to place within the liver. The aim of this project is to test the validity of a new non-invasive method of measuring and imaging the liver iron concentrations of a patient. In addition, the potential to use the new technology for detecting and imaging liver cirrhosis in iron overloaded patients will be evaluated. If successful, the project may lead to a more accurate method of measuring tissue iron concentrations and eliminate the need for invasive procedures.Read moreRead less
Too little or too much of the essential element iron is the cause of some of the most common disorders affecting humans. These include iron overload, anaemia, and anaemia of chronic disease. This project examines the genes and the roles they play in regulating iron levels in the body, and the consequences to the individuals when they are mutated. Ultimately I intend to develop therapeutics and diagnostics which will help early diagnosis and effective treatment of these disorders.
EXAMINING THE RELATIONSHIP BETWEEN MATRIPTASE-2 AND HEMOJUVELIN, TWO ESSENTIAL REGULATORS OF IRON HOMEOSTASIS
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
The control of iron levels is important in health and well being. Too little can lead to iron deficiency and anaemia, conversly too much can lead to haemochromatosis and tissue damage. We will examine the role of two proteins, matriptase-2 and hemojuvelin that when mutated cause iron deficiency or iron overload respectively. We will study how these proteins interact and work in opposite directions to control iron levels. The results will help to develop new therapeutics for iron disorders.
Deciphering Signalling Pathways Regulating Iron Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$407,402.00
Summary
Iron overload and anaemia are two of the most significant health problems affecting humans. Understanding how the body regulates iron levels is key to our understanding of these disorders and to the future development of new therapies. This research is aimed at understanding how a hormone produced in the liver called hepcidin that maintains iron balance is regulated. This research may lead to novel therapies aimed at correcting the iron balance in conditions of iron overload or anaemia.
Iron is essential for brain health. Too little iron can cause problems with memory, concentration and attention and can result in below average intellectual performance or even stroke in children. Too much iron can also be harmful. In the iron overload disease haemochromatosis, iron deposition throughout the body can lead to organ damage in the liver and other tissues. Concentrations of iron in the brain can equal those in liver. Yet surprisingly little is known about the effects of iron on the ....Iron is essential for brain health. Too little iron can cause problems with memory, concentration and attention and can result in below average intellectual performance or even stroke in children. Too much iron can also be harmful. In the iron overload disease haemochromatosis, iron deposition throughout the body can lead to organ damage in the liver and other tissues. Concentrations of iron in the brain can equal those in liver. Yet surprisingly little is known about the effects of iron on the adult human brain. Although the adult brain has traditionally been considered to be protected from the effects of high body iron by the blood-brain barrier, modern techniques show brain iron loading in patients with iron overload disorders or with various brain diseases such as Alzheimer's disease and Parkinson's disease. Several recent studies, including our own, have found associations between mutations in genes important in iron metabolism and brain diseases such as Alzheimer's disease. As many as 30% of Australians have abnormal iron levels (too high or too low) that are often undiagnosed and untreated. There is growing reason to believe these men and women are more likely to have memory problems as well as being at increased risk of brain diseases such as Alzheimer's disease. There is an urgent need for a large-scale study of the short-term and long-term effects of iron levels and related genetic factors on brain health and function. Residents of the Western Australian town of Busselton have participated in a set of health surveys since 1966. We have studied the iron status and related genetic factors in over 3,000 Busselton people. We now propose to perform tests of memory, attention, concentration and related brain activities on the older members of this community group. This will allow us to discover the effects of relevant gene factors, and short- and long-term iron status on memory and other brain functions and on Alzheimer's disease and related disorders.Read moreRead less
HFE-associated Steatohepatitis: Mechanisms And Therapies
Funder
National Health and Medical Research Council
Funding Amount
$650,813.00
Summary
Iron and fat alter normal iron metabolism and cause more severe disease in combination. In this study we will study the relationship between liver disease caused by increased body iron and the consumption of excess fat and the causal mechanisms. We will then examine new therapies for the treatment of iron-associated fatty liver disease.
By the time a patient first presents with symptoms of Parkinson's disease at the clinic, a large proportion (60-70%) of the cells in a specific part of the brain have been destroyed. This degeneration progresses until, within a few years, most of the cells have died. This project investigates the mechanisms involved in the continued death of cells and a possible new therapy that interrupts the progression. If the aims of this proposal are met, the drug could rapidly go to clinical trial.
Improving The Quality Of Nephrology Care In Rural Australia (INCRA): Implementation Of Key Guidelines Into Clinical Practice In Rural Or Remote Nephrology Practices.