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
Building An Intestine: Manipulating Regeneration Of The Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$609,424.00
Summary
Diseases, infections and pathologies are common clinical problems of the intestinal lining in both infants and adults. Individuals with these conditions can experience nutritional problems and severe cases result in death. The intestinal lining is generated from a small population of stem cells. In this study we use of a mouse model where the stem cells are marked and will examine what factors regulate stem cells in the intestine with the aim of facilitating intestinal tissue regeneration.
Exploring The Mechanisms Of Generation Of Intestinal TH17 Responses And The Mechanisms Of TH17 Mediated Pathology
Funder
National Health and Medical Research Council
Funding Amount
$617,531.00
Summary
Our research recently described a mouse that shows excellent similarities to human inflammatory bowel diseases. We further show that the disease mediating substances called cytokines are also similar between our mouse and UC. Particularly, a recently described network of cytokines that are the major mediators of disease in our mice and human IBD. This project examines how we can best interfere with the actions of these cytokines to treat and prevent intestinal inflammation.