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Iron Metabolism And The Cirrhotic Liver:studies On Iron Absorption And Hepatic Iron Kinetics
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
Patients with liver disease awaiting liver transplantation often have excess iron in the liver that aggravates the existing liver disease. We have shown that patients with cholestatic liver disease, (due to poor bile excretion), do not have much iron in the liver compared to those patients with hepatocellular cirrhosis, (where the liver cells are damaged). Why this is so is unknown. Iron is normally absorbed from the diet by with the help of special molecules in the small intestine, carried in t ....Patients with liver disease awaiting liver transplantation often have excess iron in the liver that aggravates the existing liver disease. We have shown that patients with cholestatic liver disease, (due to poor bile excretion), do not have much iron in the liver compared to those patients with hepatocellular cirrhosis, (where the liver cells are damaged). Why this is so is unknown. Iron is normally absorbed from the diet by with the help of special molecules in the small intestine, carried in the blood to the liver where it is used by the cells. We would like to study how the proteins that transport iron in the intestine function and see if this is a different in disease. We would also like to examine exactly which molecules are important in depositing iron in the liver in patients with cirrhosis. We will work on animal models of liver disease as well as humans. We will treat animals so that they have liver disease that resembles human subjects with cirrhosis. These treatments include (1) feeding the animals carbon-tetrachloride, a toxin which damages the liver cells and therefore causes hepatocellular liver injury, and (2) tying the bile duct which stops the flow of bile and this results in cholestatic liver injury. It is known which proteins takes iron into the normal liver cells but no one knows which molecules transport the iron in liver disease. We think they may be different, because when the liver becomes diseased, scarring occurs this results in cirrhosis. Molecules that could easily enter liver cells may now be too big to pass through the openings. These studies are important since they will suggest new treatments to patients with liver disease who are awaiting a liver transplant and the treatment will probably differ depending on which type of liver disease the patient has.Read moreRead less
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.
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 Chief Investigators have worked as a team for 20 years as part of a successful NHMRC Program Grant that was renewed on three successive occasions and subsequently under a NHMRC Block Grant to QIMR. Their combined expertise covers the whole spectrum from the bedside to the bench with respect to clinical studies and fundamental molecular studies of iron homeostasis. The common theme of iron homeostasis and iron overload pervades virtually all the research of the team. The team�s research has l ....The Chief Investigators have worked as a team for 20 years as part of a successful NHMRC Program Grant that was renewed on three successive occasions and subsequently under a NHMRC Block Grant to QIMR. Their combined expertise covers the whole spectrum from the bedside to the bench with respect to clinical studies and fundamental molecular studies of iron homeostasis. The common theme of iron homeostasis and iron overload pervades virtually all the research of the team. The team�s research has led to fundamental observations of iron regulation and homeostasis and the development of guidelines for the management of, and screening for, haemochromatosis, recognized as the most common inherited disorder of Caucasian populations. The proposed research encompasses molecular studies aimed at deciphering the mechanisms of iron absorption and transport; how these processes are regulated; and clinical studies on patients diagnosed with haemochromatosis. The findings are particularly pertinent to the diagnosis, management and prevention of clinical haemochromatosis.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
HLA-G/H2-Bl Is Critical For Regulating Inflammation In The Liver
Funder
National Health and Medical Research Council
Funding Amount
$494,050.00
Summary
The key factor to induction of liver fibrosis, progression to cirrhosis, and hepatocellular carcinoma is inflammation. Liver transplant and liver regeneration following liver resection are also dramatically impaired by elevation of inflammation. We have identified a potent anti-inflammatory protein, HLA-G, that is critical for regulating post-surgical inflammation in the liver. We will determine if HLA-G can reverse and/or block liver fibrosis and modify HLA-G for improved clinical potential.
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