Red Cell Disorders And The Regulation Of Iron Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
Iron is an essential nutrient, but it is also toxic when present in excess, so the amount of iron moving into and around the body must be tightly controlled. In this project we will investigate how this body iron movement is regulated, and in particular the role played by macrophages, the cells that clean up old red blood cells. An understanding of this process will be of great benefit in the analysis and treatment of important blood diseases and disorders of iron metabolism.
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-HFE Haemochromatosis In Australia: Natural History And Molecular Characterisation
Funder
National Health and Medical Research Council
Funding Amount
$179,948.00
Summary
Hereditary haemochromatosis (HH) is a disorder characterised by excessive iron absorption and build up of iron in body organs such as the liver. The excess iron can be toxic and cause disease. Most HH is caused by mutations in the HFE gene. Other forms are caused by mutations in other genes. This project will characterise a new form of HH that is unrelated to any of the previously known genes. The project aims to find the gene for this new condition by genetic analysis in a large family.
Characterisation Of The Mechanisms Of Gastrointestinal And Hepatic Iron Transport In Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
Hereditary haemochromatosis is a very common genetic disease that affects approximately 1:200 Australians. It alters the way the body uses iron. Iron is essential for health but too much iron is toxic to the body and causes harmful damage to organs. In hereditary haemochromatosis the body absorbs too much iron from the diet and most of the extra iron goes to the liver where it may cause liver cirrhosis and liver cancer. Some of the excess iron also goes to the heart, pancreas and joints where it ....Hereditary haemochromatosis is a very common genetic disease that affects approximately 1:200 Australians. It alters the way the body uses iron. Iron is essential for health but too much iron is toxic to the body and causes harmful damage to organs. In hereditary haemochromatosis the body absorbs too much iron from the diet and most of the extra iron goes to the liver where it may cause liver cirrhosis and liver cancer. Some of the excess iron also goes to the heart, pancreas and joints where it can lead to heart failure, diabetes and arthritis, respectively. There are several types of haemochromatosis that are caused by mutations in different genes that are important in the regulation of iron metabolism. In this study we will investigate two types of haemochromatosis caused by mutations in genes called HFE and transferrin receptor 2. How defects in these genes cause iron overload is not known. We will use laboratory models that have mutations in HFE and transferrin receptor 2 genes to identify for the first time how these proteins control the amount of iron the body absorbs from the diet and how much iron to delivered to the tissues such as the liver. From this study, we will gain a better understanding of the role of HFE and transferrin receptor 2 in both normal iron metabolism and haemochromatosis. This new knowledge will provide opportunities for the development of new more effective therapies for the prevention and treatment of iron overload.Read moreRead less