Mechanisms Of Intestinal And Systemic Iron Homeostasis In Early Infancy
Funder
National Health and Medical Research Council
Funding Amount
$485,835.00
Summary
Iron is essential trace element for normal health. Iron requirements are particularly high during early postnatal life to meet the needs of the growing infant. To accommodate these needs, intestinal iron absorption is extremely high at this time. We have previously shown that the iron absorption mechanism during suckling differs from that in adults and this project explores that mechanism in more detail. These studies have important implications for infant nutrition and dietary supplementation.
Role Of Non-transferrin Bound Iron In Iron Overload Disease
Funder
National Health and Medical Research Council
Funding Amount
$669,504.00
Summary
Plasma non-transferrin bound iron (NTBI) levels are elevated in iron overload disorders. Excess NTBI has serious health consequences as it is toxic and may induce cellular dysfunction and injury. We will investigate the molecular mechanisms by which NTBI transport is regulated, the contribution of NTBI to the development of iron overload and its impact on oxidative-mediated liver and heart injury in iron overload conditions associated with Hereditary Haemochromatosis and thalassaemia.
The Mechanism Of Intestinal Haem Iron Absorption And Characterization Of A Novel Haem-binding Protein
Funder
National Health and Medical Research Council
Funding Amount
$537,773.00
Summary
Iron is essential for normal health as many important proteins in the body require iron to function properly (e.g. haemoglobin). However, too much iron can be toxic, so the body must keep its iron content within defined limits. The amount of iron in the body is determined at the point of absorption from the diet in the small intestine. If too little iron is absorbed, then anaemia can result. If too much iron is absorbed, as is the case in the common disease haemochromatosis (with approximately 1 ....Iron is essential for normal health as many important proteins in the body require iron to function properly (e.g. haemoglobin). However, too much iron can be toxic, so the body must keep its iron content within defined limits. The amount of iron in the body is determined at the point of absorption from the diet in the small intestine. If too little iron is absorbed, then anaemia can result. If too much iron is absorbed, as is the case in the common disease haemochromatosis (with approximately 1 in 200 Australians at risk) then the body becomes iron loaded and various organs, particularly the liver, can become damaged. An understanding of how iron is absorbed will place us in a much better position to treat diseases such as this. Iron is present in the diet in two forms - inorganic iron and haem iron. Inorganic iron is the main form of iron in foods of plant origin while most haem iron comes from meat. In a typical diet 80-90% of the iron is inorganic iron and only 10-20% is haem. Despite this, 30-50% of the iron taken into the body comes from haem, so haem iron absorption is particularly efficient. While we have learned a great deal about the mechanims by which inorganic iron is absorbed in recent years, we know very little about the absorption of haem iron, so that is the focus of this project. We will study the pathway by which haem enters the body, how this process is regulated, and the characteristics of haem binding to the cells lining the small intestine. These cells are responsible for the uptake of all nutrients from the diet. In particular, we will examine the biology of a recently identified protein known as HCP1. Preliminary evidence suggests that HCP1 could be the main protein enabling haem to be taken up by intestinal cells. These studies will enhance our knowledge of an important nutritional pathway and improve our capacity to treat diseases such as haemochromatosis where iron absorption is defective.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
Iron is essential in the diet but it is also toxic when present in excess, so both iron deficiency and iron overload can have significant clinical consequences. I will investigate the basic mechanisms by which the body acquires iron and how iron can lead to toxicity. The goal of these studies is to provide more effective iron supplements and to improve diagnosis and treatment of iron-related diseases. Iron metabolism in pregnancy, infants and respiratory diseases will be a particular focus.
Targeting Iron Piracy From Host Proteins By Neisseria And Haemophilus Spp. For The Development Of Novel Antimicrobials
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
The bacteria that cause the sexually transmitted infection gonorrhoea and meningococcal disease are a serious health concern. In order to cause disease, these bacteria must obtain the nutrient iron from our bodies. This proposed research will use cutting edge technologies to understand on a molecular level how these bacteria obtain iron during infection. It will then apply this knowledge to develop molecules that prevent these bacteria from obtaining iron, as a means of treating these diseases.
Transport Pathways Of Host-derived Iron In Schistosomes Parasites
Funder
National Health and Medical Research Council
Funding Amount
$322,091.00
Summary
This project will identify the diversity and biological roles of receptors for metabolic iron expressed on the body surface of the parasitic blood flukes (schistosomes) of humans. Schistosomes are a major health problem in many tropical countries and are responsible for significant human morbidity and lost productivity. Adult worms feed on human blood, from which derive amino acids for the production of many hundreds of eggs released per day into the human blood stream. The intense cellular resp ....This project will identify the diversity and biological roles of receptors for metabolic iron expressed on the body surface of the parasitic blood flukes (schistosomes) of humans. Schistosomes are a major health problem in many tropical countries and are responsible for significant human morbidity and lost productivity. Adult worms feed on human blood, from which derive amino acids for the production of many hundreds of eggs released per day into the human blood stream. The intense cellular response induced by parasite eggs trapped in body organs is the major cause of chronic human disease. We have discovered two intriguing phenomena of iron metabolism in schistosomes. Firstly, schistosomes have a greater reliance on iron than many other organisms, storing a surfeit in cells that produce the protein-rich egg shell. Secondly, a major transmembrane iron transporter of the parasites, thought to be involved in the uptake of iron, is found on the parasite external body surface and not in the parasite intestine. The extensive nutritional dependence of these worms on iron and the surface location of mediators of iron uptake raise the exciting possibility that we have uncovered a novel system that might be exploited for vaccine or drug-mediated control of these significant human parasites. If we can dissect the pathways schistosomes use to derive iron from their hosts, we may be able to generate vaccines to block this nutritional pathway, or use drugs to block embryogenesis. This project is a fact-finding mission that asks if the host-interactive tegument of these parasites is a major source of metabolic iron. Molecules we demonstrate to be present on the surface will be tested as vaccine candidates in mouse vaccine trialsRead moreRead less
Mechanism Of Anoxic Iron Acquisition In Pathogenic Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$536,280.00
Summary
All organisms require iron for their survival, including all bacterial species. Bacterial pathogens growing in anaerobic environments, such as in our gut, gum, or tissue, sequester iron through the divalent iron transporter FeoB. We aim to divulge the mechanism of iron transport through FeoB by structural and functional studies, and thus provide a scaffold for a non-conventional antimicrobial target.