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
Mechanisms Of Intestinal Iron Absorption And Consequences Of Iron Supplementation During The Perinatal Period
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Iron intake is particularly high during pregnancy and in the newborn to meet the requirements of the growing fetus and neonate. While it is widely recommended that women take iron supplements at this time, too much iron may adversely affect pregnancy outcome. The aim of this study is to understand the factors controlling iron intake in the perinatal and the consequences of excess iron. This will provide the physiological information required to make rational decisions about iron supplementation.
The Pathogenesis Of Haemochromatosis In The HFE Knockout Mouse Model
Funder
National Health and Medical Research Council
Funding Amount
$244,616.00
Summary
Hereditary haemochromatosis is a very common genetic disease that affects approximately 1 in 200 Australians. It alters the way the body uses iron. It causes an increase in absorption of dietary iron and increased deposition of iron in major organs of the body such as the liver, heart and pancreas. This iron is harmful to tissues in the body and may lead to the development of liver cirrhosis, heart disease, diabetes and malignancy. The gene that is defective in hereditary haemochromatosis patien ....Hereditary haemochromatosis is a very common genetic disease that affects approximately 1 in 200 Australians. It alters the way the body uses iron. It causes an increase in absorption of dietary iron and increased deposition of iron in major organs of the body such as the liver, heart and pancreas. This iron is harmful to tissues in the body and may lead to the development of liver cirrhosis, heart disease, diabetes and malignancy. The gene that is defective in hereditary haemochromatosis patients has been identified and called HFE however, the function of HFE is not known. Recently, an excellent laboratory model of this disease has been developed. We aim to use this model to show for the first time how HFE controls the amount of iron the body absorbs and how much iron is delivered to tissues such as the liver. We also aim to identify how these processes are impaired in hereditary haemochromatosis patients. From this study, we will gain a better understanding of the role of HFE in iron metabolism of normal and hereditary haemochromatosis patients and this will provide opportunities for the development of new therapies for the prevention or treatment of iron overload.Read moreRead less
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
ProbioticTreatment Of Diarrhoeal Disease And Malnutrition In Top End Aboriginal Children
Funder
National Health and Medical Research Council
Funding Amount
$332,036.00
Summary
Aboriginal children in the Top End of Australia have high rates of hospital admission for diarrhoea and malnutrition. We have discovered that underlying small intestinal damage in these children is an important contributor to the high complication rates and longer lengths of stay in hospital compared to non-Aboriginal children. This research proposes to continue our work on small intestinal damage by using two non-invasive tests of gut function, namely a sugar absorption test and novel breath te ....Aboriginal children in the Top End of Australia have high rates of hospital admission for diarrhoea and malnutrition. We have discovered that underlying small intestinal damage in these children is an important contributor to the high complication rates and longer lengths of stay in hospital compared to non-Aboriginal children. This research proposes to continue our work on small intestinal damage by using two non-invasive tests of gut function, namely a sugar absorption test and novel breath test. The sugar permeability test involves the children drinking a solution of the two sugars lactulose and rhamnose, and measuring their absorption into the blood 90 minutes later using a sophisticated measuring instrument called HPLC, which can measure minuscule amounts of sugars and is set up at Royal Darwin Hospital. The breath test involves children drinking another sugar solution with a special non-radioactive marker called a stable isotope of carbon, and measuring changes in the amount of this marker in carbon dioxide from the breath at timed periods after drinking the sugar solution. The breath is analysed in Adelaide using another sophisticated instrument. These tests are being used to measure abnormal sugar absorption due to intestinal damage, which is particularly common in Aboriginal children during the weaning period of 4-18 months. Our hypothesis is that treatment with 'healthy germs' (probiotics) like those in certain yoghourts will colonise the gut, stimulate immunity and reduce the presence of 'nasty germs' (pathogenic bacteria) in the intestines of Aboriginal children which contribute to the need for their hospitalisation with diarrhoea and malnutrition. If this hypothesis is correct, then this research will provide the best kind of evidence for reducing the need for hospital treatment by treating all cases of diarrhoea with these probiotics and possibly even decreasing the gut damage of children in the weaning period by including probiotics in their dietsRead moreRead less
Copper is an essential trace element with the potential for toxicity. Copper deficiency can be fatal to developing animals due to the multiple organ abnormalities caused by the reduced activity of important copper containing enzymes. Dietary copper deficiency can cause iron unresponsive anaemia in children and may contribute to heart disease and connective tissue defects in adults. A variant form of a copper containing protein is thought to contribute to Alzheimer's disease and the affected prot ....Copper is an essential trace element with the potential for toxicity. Copper deficiency can be fatal to developing animals due to the multiple organ abnormalities caused by the reduced activity of important copper containing enzymes. Dietary copper deficiency can cause iron unresponsive anaemia in children and may contribute to heart disease and connective tissue defects in adults. A variant form of a copper containing protein is thought to contribute to Alzheimer's disease and the affected protein in mad cow disease may normally play a role in copper biology of the brain. Given the importance of copper for normal health and the potential for toxicity, the levels of copper in the body are tightly regulated. There are two main sites for this regulation: the uptake of dietary copper across the intestine and the excretion of excess copper into the bile. This proposal addresses the molecular control of copper uptake in the intestine. Much of our understanding about the regulation of the uptake of copper from dietary sources was obtained prior to the era of modern molecular biology. Prof. Mercer's laboratory has recently made significant discoveries into the molecular basis of copper metabolism in human cells. Based on these findings and finding of others about copper metabolism in yeast, we have proposed a model incorporating these newly described molecules to explain how the body might regulate the uptake of copper in the intestine. We propose to investigate this model using cell culture models of the intestine and in mouse models. These studies will extend our knowledge of copper biology and may provide insight for potential treatments of copper related disorders.Read moreRead less
The Role Of Dietary FODMAPs In The Genesis Of Symptoms In Patients With Irritable Bowel Syndrome And Crohns Disease.
Funder
National Health and Medical Research Council
Funding Amount
$418,818.00
Summary
Irritable bowel syndrome occurs in one in seven Australian adults. Crohn's disease affects 0.2% of the population. Both conditions affect the young and productive members of our society and are characterised by lower abdominal pain, bloating, wind and altered bowel habit. Our team has identified dietary triggers that may be responsible for the induction of symptoms in the majority of patients. These triggers involve a group of carbohydrates (FODMAPs) that are found in a wide variety of food.
Spatio-temporal Analysis Of Rat Intestinal Motility In Physiological And Disease Models
Funder
National Health and Medical Research Council
Funding Amount
$358,750.00
Summary
This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping ....This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping behaviour to prevent over-filling or to eject toxic or irritating substances (eg: some laxatives activate this mechanisms). This is often called peristalsis. A third mechanism consists of activity of nerve cells in the gut, that slowly propagates along the intestine and causes the muscle to contract, sweeping along any remnants. The movements generated by these three mechanisms occur in segments of intestine isolated from rats. The major difficulty up until now has been to relate the actual movements in living animals to these fundamental mechanisms. It is now possible to bridge this gap because we have developed methods to record, display and measure graphically the actual movements. Movements are transformed into spatio-temporal maps which show all of the contractions over a period of time. Coordinated activity is visible in these maps as recognisable patterns or visual objects. Measurements can be readily made with conventional statistics. The literature in gastroenterology is full of descriptions of motility based on indirect methods of recordings. In this project we will be able to correlate the previous indirect methods with the new graphic methods and thus establish a clearer, simpler and more accurate classification of normal patterns of intestinal motility. We will then use this to establish what goes wrong in a number of experimental diseases known to affect adversely the movements of the intestine.Read moreRead less
Effects Of Ischemia/ Reperfusion Injury On Enteric Neurons And Neuroprotective Strategies
Funder
National Health and Medical Research Council
Funding Amount
$566,277.00
Summary
The intestine can suffer restricted blood flow, creating a region of damaged or dead bowel. This leads to severe medical emergencies, complications and even death. Loss of blood flow and damage can be a serious complication for intestinal transplant surgery, which compromises patient survival and recovery. The project brings together transplant surgeons and basic scientists to solve problems caused by intestinal ischemia. A major result will be to improve outcomes for Australian patients