Development And Characterization Of Gallbladder Epithelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$729,227.00
Summary
Death of insulin-producing cells is a common feature of type 1 and type 2 diabetes, affecting over a million Australians. Although transplantation of cadaveric human islets offers cure, lack of donor islets is a major limitations. An alternative is to find other sources of insulin-producing cells. We are the first to demonstrate that insulin-producing cells are naturally found in human gallbladder. This research proposal will involve detailed characterization of human gallbladder-derived insulin ....Death of insulin-producing cells is a common feature of type 1 and type 2 diabetes, affecting over a million Australians. Although transplantation of cadaveric human islets offers cure, lack of donor islets is a major limitations. An alternative is to find other sources of insulin-producing cells. We are the first to demonstrate that insulin-producing cells are naturally found in human gallbladder. This research proposal will involve detailed characterization of human gallbladder-derived insulin-producing cells.Read moreRead less
Physiological Function Of Nedd4-2 In Regulating The Epithelial Sodium Channel
Funder
National Health and Medical Research Council
Funding Amount
$805,797.00
Summary
The epithelial sodium channel (ENaC) controls sodium balance, blood volume and blood pressure. Abnormal regulation of ENaC is associated with conditions such as hypertension and pulmonary oedema. Delineating the regulation of ENaC is vital in understanding disease mechanisms and in defining targets for novel therapeutics for the treatment of disorders that arise due to sodium imbalance. This grant will enable us to understand how ENaC is regulated by a novel protein known as Nedd4-2.
The Physiological And Pathophysiological Roles Of Melanotransferrin
Funder
National Health and Medical Research Council
Funding Amount
$513,437.00
Summary
Melanotransferrin (MTf) is a membrane-bound molecule that was originally identified at very high levels in malignant melanoma cells and other tumours. To our surprise, our recent studies showed that MTf was also widely expressed in normal tissues (DR EJB 2000). MTf has many similarities to the iron (Fe)-binding protein, transferrin (Tf), and initially, MTf was thought to play a critical role in Fe uptake that is crucial for DNA synthesis. However, we demonstrated that MTf did not play a major ro ....Melanotransferrin (MTf) is a membrane-bound molecule that was originally identified at very high levels in malignant melanoma cells and other tumours. To our surprise, our recent studies showed that MTf was also widely expressed in normal tissues (DR EJB 2000). MTf has many similarities to the iron (Fe)-binding protein, transferrin (Tf), and initially, MTf was thought to play a critical role in Fe uptake that is crucial for DNA synthesis. However, we demonstrated that MTf did not play a major role in Fe uptake by melanoma cells (DR 1990, 1991a,b, 2000). We also showed that the tissue distribution of MTf was very different to Tf and the Tf-receptor 1 (TfR1) that are well known to be involved in Fe transport. For instance, TfR1 is highly expressed in tissues with large Fe needs (e.g., placenta), while MTf is not expressed at high levels in these tissues and is found in unexpected locations (i.e., salivary gland). In contrast to expectations, MTf was also found at higher levels in normal than foetal tissue. Also interesting was the finding that MTf is found in the serum and brain of Alzheimer's disease patients. Over the last 2 years under our current NHMRC grant on MTf we have significantly extended our knowledge on this molecule. As proposed in this grant, we generated a MTf knockout mouse. This is a very exciting model that is the best way of determining the function of MTf. Furthermore, we used recombinant MTf to show that soluble MTf that is found in the plasma is not an effective Fe donor to cells (DR EJB 2002). Our results over the last 12 years indicate that MTf may play unexpected biological roles (see DR FEBS Lett 2000). For the first time, generation of our MTf knockout mouse will provide the exciting opportunity of characterising its role(s). This will be important in understanding the function of MTf in cancer cells, Alzheimer's disease and in other tissues (eg., salivary gland and kidney) where it is expressed at high levels.Read moreRead less
Nocturnin: A Post-transcriptional Regulator Of Circadian Fat Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$574,696.00
Summary
Our metabolism is aligned with the 24-hour rotation of the earth in what is termed the circadian clock. Being misaligned to this clock explains jetlag and the poor health associated with shift-workers. For example, whether fat is utilised or stored depends on the time of day. This study aims to investigate the post-transcriptional mechanisms that underpin the rhythmic changes that occur throughout our bodies to ensure that our metabolism is matched to our environment.
Metabolic Wiring In Adipocytes - Unique Role In Maintaining Long-term Health
Funder
National Health and Medical Research Council
Funding Amount
$1,077,886.00
Summary
Fat cell metabolism is wired to optimize the cell’s ability to make and store lipid while programming the cell to fulfil its function in whole body metabolism. We will: 1) map fat cell metabolism under optimal and insulin resistant conditions; 2) explore the role of 3 nodes in his metabolic circuit predicted as control points; 3) use a novel genetically engineered mouse model to explore the functional significance of fat cell metabolism in whole body insulin sensitivity.
Mammalian cells have developed a complex signalling network responsible for monitoring and responding to changes in the levels of growth factors and the availability of nutrients, energy and oxygen in their environment. Deregulation of this network often results in uncontrolled cell growth and diseases including cardiac hypertrophy and cancer. This proposal aims to understand how this network controls cell growth and identify potential targets for diseases driven by uncontrolled growth.
Targeting The Class IIa Histone Deacetylases In Metabolic Disease
Funder
National Health and Medical Research Council
Funding Amount
$408,388.00
Summary
Dysfunctional metabolism in skeletal muscle is integral in the development of metabolic diseases, such as obesity and type 2 diabetes. This project will examine proteins that alter the way genes are expressed for their role in dysfunctional metabolism in muscle. This project could uncover new therapies for the treatment of metabolic diseases.
Alterations In Secretion And Gene Expression In Pancreatic Beta Cells Exposed To Lipid.
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The project is aimed at a better understanding of the way in which fats control gene expression in the pancreatic beta cells of the islets of Langerhans. Because changes in gene expression are to likely to explain why exposure of these cells to fat disrupts their ability to release insulin, identification of these genes could explain why only some obese people develop Type 2 diabetes.
Control Of The Cholesterol Esterification Cycle In Macrophages
Funder
National Health and Medical Research Council
Funding Amount
$150,660.00
Summary
Atherosclerosis is the disease which narrows arteries and causes heart attacks. It is the most important cause of death in Australia. Although certain treatments such as lowering blood cholesterol reduce the incidence of heart attack, the current mortality from this conditions indicates that there is a great need to improve our understanding and treatment of atherosclerosis. In atherosclerotic arteries, cells called macrophages contain excess cholesterol in the form of cholesteryl ester droplets ....Atherosclerosis is the disease which narrows arteries and causes heart attacks. It is the most important cause of death in Australia. Although certain treatments such as lowering blood cholesterol reduce the incidence of heart attack, the current mortality from this conditions indicates that there is a great need to improve our understanding and treatment of atherosclerosis. In atherosclerotic arteries, cells called macrophages contain excess cholesterol in the form of cholesteryl ester droplets. It appears that human cells are very inefficient at clearing such cholesteryl esters, and this may explain why atherosclerosis is difficult to treat. In this proposal we will investigate how macrophages metabolise these cholesteryl esters and how this process can be stimulated. The results of this study should enable novel treatments of this serious condition to be developed.Read moreRead less