REGULATION AND NOVEL FUNCTIONS OF INDOLEAMINE 2,3-DIOXYGENASE
Funder
National Health and Medical Research Council
Funding Amount
$268,403.00
Summary
We are studying a protein important in the host's response to infections. The expression of this protein which degrades the least abundant of all essential amino acids, is increased dramatically in inflammatory disorders, and plays a role in the control of cell growth. The protein and products produced along the metabolic pathway it induces have many additional interesting properties, similar to those of another pathway. We propose that these two pathways are functionally related and how the pro ....We are studying a protein important in the host's response to infections. The expression of this protein which degrades the least abundant of all essential amino acids, is increased dramatically in inflammatory disorders, and plays a role in the control of cell growth. The protein and products produced along the metabolic pathway it induces have many additional interesting properties, similar to those of another pathway. We propose that these two pathways are functionally related and how the protein of interest is regulated. We will test this directly using purified proteins, isolated cells, and animal studies and employing sophisticated techniques ranging from physical chemistry to molecular biology. We will also examine possible new functions of our protein of interest. These studies will allow us to find ways to regulate the protein and this may be relevant to diseases such as infections and the hardening of arteries.Read moreRead less
Post-translational Control Of Indoleamine 2,3-dioxygenase
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
It is apparent that a protein called indoleamine 2,3-dioxygenase is important for controlling the immune system of relevance to various normal and disease conditions including pregnancy, cancer, inflammation, infectious disease and autoimmunity. Despite this little is known about how this important protein is controlled. The aim of this project is to better understand how this protein is regulated that can highlight ways in which to alter the enzymes activity to modulate immune responces.
Regulation Of Vascular Tone By Indoleamine 2,3-dioxygenase
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other condit ....As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other conditions, including certain diseases, so that it is not surprising that many of the commonly used cardiovascular drugs target to change blood vessel tone, either increasing or decreasing blood pressure, depending on the circumstances involved. The present application is based on the discovery, in the mouse, that during a systemic infection a specific protein is induced in the cells that line blood vessels. This protein degrades a certain amino acid into a novel chemical, called kynurenine. We observed that kynurenine has previously unrecognised vessel-relaxing properties. The present project will investigate the importance of kynurenine formation as a novel pathway in the regulation of vascular tone. Mice, in which the activity of the kynurenine-producing protein will be modulated (both up and down) will be used in conjunction with blood pressure and other relevant measurements. In addition, the role of a unique molecule, called superoxide anion radical, in the production of kynurenine by the protein will also be tested. If our results confirm that the protein and kynurenine are indeed involved in regulating vascular tone, our research could have tremendous impact on many aspects of normal physiology as well as cardiovascular diseases that remain the major single cause of death in Australia.Read moreRead less
Role Of Tryptophan Metabolism In Liver Transplant Tolerance And Rejection
Funder
National Health and Medical Research Council
Funding Amount
$401,203.00
Summary
Many thousands of Australians have a failing liver and the only treatment for this is a liver transplant. Liver transplantation is a major life-saving strategy and hundreds of Australians are rescued each year who would otherwise have died. Rejection of the transplant is the major problem affecting these patients. This project investigates an animal model where a transplanted rat liver is not rejected, even though the recipient receives no treatment. Previous studies from our group have shown th ....Many thousands of Australians have a failing liver and the only treatment for this is a liver transplant. Liver transplantation is a major life-saving strategy and hundreds of Australians are rescued each year who would otherwise have died. Rejection of the transplant is the major problem affecting these patients. This project investigates an animal model where a transplanted rat liver is not rejected, even though the recipient receives no treatment. Previous studies from our group have shown that acceptance is due to donor white blood cells transferred with the liver and based on this finding we are developing treatments that can be used in transplant patients. The current application for funding tests another breakthrough that we have recently made, that treatment of the recipient with a substance called 1-methyltryptophan prevents liver acceptance. 1-methyltryptophan prevents the activity of an enzyme called indoleamine dioxygenase, which we have shown to be increased in liver recipients that accept their graft. This is strong evidence that indoleamine dioxygenase is involved in liver transplant tolerance. These findings show that liver acceptance should be improved by increasing the levels of indoleamine dioxygenase at the time of transplantation. The aim of the current application is to examine whether increased levels of indoleamine dioxygenase expression in the transplanted liver can lead to an improved outcome. We will use two novel techniques to increase expression: gene therapy or treatment of the donor with IL-4. For gene therapy, an expression system will be used that we have recently shown is specific for the liver. In current NHMRC-funded experiments we have shown that IL-4 treatment of donor liver leads to marked increases in indoleamine dioxygenase expression. Ultimately it is intended that these findings will be used to prolong the survival of liver transplant patients by revealing new ways to prevent rejection of liver transplants.Read moreRead less
Role Of Indoleamine 2,3-dioxygenase In Vascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$271,500.00
Summary
Atherosclerosis and its clinical presentation including heart attack and stroke represent a major source of morbidity and mortality in the developed world, including Australia. Atherosclerosis involves the accumulation of lipid-laden cells in the wall of arteries that generates plaques resulting in a decrease in the lumen of the affected vessel that can impede or block blood flow resulting in clinical complications. The cellular events involved in atherosclerosis are complex. However, increasing ....Atherosclerosis and its clinical presentation including heart attack and stroke represent a major source of morbidity and mortality in the developed world, including Australia. Atherosclerosis involves the accumulation of lipid-laden cells in the wall of arteries that generates plaques resulting in a decrease in the lumen of the affected vessel that can impede or block blood flow resulting in clinical complications. The cellular events involved in atherosclerosis are complex. However, increasing information indicates that atherosclerosis involves an inappropriate response of the immune and inflammatory systems. This proposal plans to investigate the role of a protein, indoleamine 2,3-dioxygenase (IDO) that is increased during inflammation and is important for the regulation of the host's immune system. We propose that increasing IDO activity in inflammatory cells will attenuate the degree of vascular disease by decreasing the overall level of immune activation and inflammation in the blood vessels. We will test this by modulating the expression and activity of this protein in animal models of vascular disease, measure the extent of disease and then elucidate the mechanisms by which the protein acts. The significance of these studies is that they will provide useful information on the inflammatory and immune processes involved in the progression of atherosclerosis and may identify a potential novel target for therapeutic intervention.Read moreRead less
We have found that during infection a protein (called IDO) is made in cells lining arteries. IDO degrades tryptophan into kynurenine, which can open arteries, while blocking IDO increases blood pressure. We will now study the importance of this metabolic pathway in various diseases using mice with either absent or high levels of IDO, and also perform the first such studies in human blood vessels. We predict the research to have a tremendous impact on our understanding of cardiovascular diseases.