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
The Role Of The Liver In The Pathogenesis Of Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$592,023.00
Summary
Hereditary Haemochromatosis (HH) type 1 is a very common inherited disorder of iron metabolism that affects 1:200 Australians. HH is usually caused by mutations in the HFE gene and leads to excessive absorption of dietary iron and progressive iron loading of organs, particularly the liver. Undetected, progressive iron accumulation may have serious clinical consequences including cirrhosis, arthritis, diabetes mellitus and heart disease. The role of HFE in normal iron metabolism and how mutations ....Hereditary Haemochromatosis (HH) type 1 is a very common inherited disorder of iron metabolism that affects 1:200 Australians. HH is usually caused by mutations in the HFE gene and leads to excessive absorption of dietary iron and progressive iron loading of organs, particularly the liver. Undetected, progressive iron accumulation may have serious clinical consequences including cirrhosis, arthritis, diabetes mellitus and heart disease. The role of HFE in normal iron metabolism and how mutations in HFE lead to the development of Fe overload are unknown. Other types of HH have been identified that have similar clinical characteristics to HH type 1 which are due to mutations in hepcidin or haemojuvelin (type 2) and transferrin receptor 2 genes (type 3). It is thought that HFE acts together with these molecules in the same or closely related pathways to regulate iron metabolism. It is hypothesised that HFE and transferrin receptor 2 act as sensors of body iron levels which signal to the iron stores regulator, hepcidin to control the absorption of dietary iron and the deposition of iron in the liver. In this study, we will use mice with mutations in HFE and transferrin receptor 2 which have many of the characteristics of human HH type 1 and type 3 to identify 1) how HFE and transferrin receptor 2 sense body iron levels, 2) how they signal to hepcidin to regulate iron metabolism and 3) how mutations in HFE and transferrin receptor 2 lead to dysfunctional sensing of iron levels and impaired signalling to hepcidin causing increased iron absorption and liver iron overload in HH. This study will provide new knowledge about the role of HFE and other closely related molecules in the regulation of normal iron metabolism and the development of iron overload in HH and identify the potential of molecules such as hepcidin for therapeutical use for the prevention and treatment of iron overload.Read moreRead less
The Role Of Transferrin Receptor, Divalent Metal Transporter, Ferroportin And Hemochromatosis Protein In Iron Absorption
Funder
National Health and Medical Research Council
Funding Amount
$195,990.00
Summary
Within Australia 1 in 300 people of Caucasian origin have a genetic defect which makes them absorb more iron from the diet than they need. Excess iron is a major problem because it damages cells and this is most obvious in the pancreas where the cells make insulin are destroyed and diabetes mellitus develop. In the liver cirrhosis and cancer often occur. Iron also accumulates in other tissues such as the heart and joints resulting in damage to these organs. The genetic defect has recently been i ....Within Australia 1 in 300 people of Caucasian origin have a genetic defect which makes them absorb more iron from the diet than they need. Excess iron is a major problem because it damages cells and this is most obvious in the pancreas where the cells make insulin are destroyed and diabetes mellitus develop. In the liver cirrhosis and cancer often occur. Iron also accumulates in other tissues such as the heart and joints resulting in damage to these organs. The genetic defect has recently been identified but how the defective protein causes the cells of the intestine to absorb more iron into the body than is needed remains unknown. This has led to the idea that the normal protein is responsible for controlling the amount of iron absorbed. Recent studies have shown a link between this protein and another called transferrin receptor. These two molecules are thought to co-operate in determining how much iron will be absorbed. Once this is determined other molecules called iron transporters are produced and these are responsible for moving the iron from the intestine into the blood. When not much iron is required only a small number of transporters are made and when more iron is required then many more are produced. How these transporters program the level of iron absorption is unknown but the process probably involves the transferrin receptor and the hemochromatosis protein. This project will investigate the function of the molecules that determine the programe for how much iron is to be absorbed, and secondly how this is linked to the production and movement of the transproters that co-ordinate this function.Read moreRead less
Using Nanotechnology To Improve The Therapeutic Efficacy Of Iron Chelators
Funder
National Health and Medical Research Council
Funding Amount
$692,769.00
Summary
Iron loading disorders (such as thalassaemia) represent an important class of human disease. As part of the treatment for these diseases, the iron needs to be removed and this is often done using iron-binding drugs known as iron chelators. Current chelators are not ideal due to side effects or onerous delivery methods. The goal of this project is to use nanotechnology to develop more effective ways of delivering chelators to improve their effectiveness and reduce toxicity.
Environmental Risk Factors For Iron Overload-related Disease In A Cohort Study Of Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$152,936.00
Summary
Results published last year from our Melbourne HealthIron study of hereditary haemochromatosis (iron overload disease) show that almost one third of the 50,000 men genetically at risk of iron overload in Australia will develop symptoms of disease including fatigue, arthritis and liver damage. We will use data from the recent follow-up of the Health2020 cohort, of which HealthIron is a sub-study, to determine environmental risk factors for progression to disease in people with iron overload.
Early Versus Delayed Therapeutic Venesection For The Prevention Of Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$196,012.00
Summary
This study will investigate treatment by blood removal for the inherited iron overload condition hereditary haemochromatosis: Is treatment more effective in reducing risk of disease if performed early as a preventive measure rather than later after diagnosis with symptoms? Details of the lifetime history of blood donation from the Australian Red Cross Blood Service will be combined with existing information from questionnaires and clinical examination of 1,439 study participants in Melbourne.
My research focuses on mechanisms of intestinal iron absorption and its regulation, with a particular emphasis on understanding human disorders where iron homeostasis is perturbed.