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Role Of Nuclear Receptors In Hepatic Injury And Fibrogenesis
Funder
National Health and Medical Research Council
Funding Amount
$443,520.00
Summary
Chronic liver disease is a major cause of death and ill health on a word-wide scale. Several common liver diseases, such as hepatitis B, hepatitis C and non-alcoholic steatohepatitis (fatty liver disease not due to alcohol), are capable of causing protracted liver damage. Irrespective of the cause of injury, the liver has a very narrow way of responding to chronic damage. The most important and insidious of these is hepatic fibrosis (scarring), which, along with liver regeneration, eventually le ....Chronic liver disease is a major cause of death and ill health on a word-wide scale. Several common liver diseases, such as hepatitis B, hepatitis C and non-alcoholic steatohepatitis (fatty liver disease not due to alcohol), are capable of causing protracted liver damage. Irrespective of the cause of injury, the liver has a very narrow way of responding to chronic damage. The most important and insidious of these is hepatic fibrosis (scarring), which, along with liver regeneration, eventually leads to cirrhosis if the injurious process is sufficiently intense and sustained. Liver cirrhosis is the precursor to several undesirable complications of liver disease, most notably primary liver cancer (also called hepatoma), liver failure and severe bleeding from the gut. Therefore, it is not surprising that effective strategies to control liver injury and prevent cirrhosis have been called the holy grail of liver research. To date the only therapies for substantially improving the outcome of patients with chronic liver disease are those that halt or remove the cause of injury. Unfortunately, in many cases it is still not possible to remove or effectively treat the cause of injury. Because of this there is intense interest in therapies that might favourably alter the response of the liver to injury and especially in those that may retard or inhibit scarring and prevent cirrhosis. Nuclear receptors are sensors that control many aspects of the body's metabolism, especially the metabolism of cholesterol and fat. Recently, our work and that of others has suggested that some nuclear receptors may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so, and which of the several nuclear receptors likely to be involved are the important ones. We will then extend these studies to see if drugs that activate these receptors will improve or prevent severe liver disease.Read moreRead less
Repression Of Hepatic Drug Metabolism By Solid Tumours
Funder
National Health and Medical Research Council
Funding Amount
$504,000.00
Summary
The treatment of advanced cancer patients with drugs is difficult due to many confounding factors. The variability between patients in clearance rate has a significant impact on the success of chemotherapy. This is especially relevant to chemotherapeutic agents which have a narrow therapeutic range. Anti-tumour action will be lost if the drug is cleared too rapidly from the body, while high doses will lead to toxic side effects. A better understanding of the source of this variability will lead ....The treatment of advanced cancer patients with drugs is difficult due to many confounding factors. The variability between patients in clearance rate has a significant impact on the success of chemotherapy. This is especially relevant to chemotherapeutic agents which have a narrow therapeutic range. Anti-tumour action will be lost if the drug is cleared too rapidly from the body, while high doses will lead to toxic side effects. A better understanding of the source of this variability will lead to improvements in the manner in which chemotherapy is administered and would represent a welcome advance for cancer patients. The rate of breakdown of drugs in the body is largely determined by the levels of enzymes called cytochrome P450s (CYPs) in the liver. In humans CYP3A4 is responsible for the disposal of more than half of all drugs including several important chemotherapeutic agents. Clinical studies have found that the presence of an inflammatory response to tumours in tissues outside the liver reduces hepatic CYP3A4 activity. Factors released by immune as well as malignant cells within the tumour circulate via the bloodstream to the liver where they alter expression of many genes including CYPs. The study of the regulation of human genes is inherently difficult. It is nearly impossible to gain access to many body tissues in either healthy or sick individuals to examine co-ordinated gene function (or dysregulation). For this reason we made a transgenic mouse model of human CYP3A4 regulation which enables the human situation to be studied. In this project we will identify the tumour-derived factors which switch off the CYP3A4 transgene and analyse the signalling pathways within liver cells which mediate the response. A knowledge of this mechanism will permit the rational design of therapeutic strategies aimed at making chemotherapy safer and more effective. The availability of convenient animal models enables testing prior to clinical application.Read moreRead less
Improving The Use Of Chemotherapy By Targeting The Inflammatory Response
Funder
National Health and Medical Research Council
Funding Amount
$570,876.00
Summary
Patient differences in clearance of anti-cancer drugs have a major impact on the success of chemotherapy. Benefit is lost if the drug is cleared too rapidly, while slow elimination causes toxicity. We will use well characterised mouse models that mirror the human situation to study the causes and effects of reduced drug metabolism in cancer. The data will guide future human studies that will result in improved diagnostic and therapeutic interventions to improve the tolerance of chemotherapy.
Steroidogenic Factor-1, A Novel Regulator Of Hepatic Stellate Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$589,458.00
Summary
Recently, we have discovered that steroidogenic factor-1, a specialized protein that directs cells to make steroid hormones, is present in cells in the liver called stellate cells. This may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so and how this system functions. This work will provide a basis for future treatments to improve or prevent cirrhosis in liver disease patients.
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
Function Of The Vitamin D Receptor In Hepatic Non-Parenchymal Cells
Funder
National Health and Medical Research Council
Funding Amount
$509,304.00
Summary
Nuclear receptors are sensors that control many aspects of metabolism, including responses to injury. Our work and has suggested that the Vitamin D Receptor (VDR) may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so, and in which cells VDR has this role. This work will provide a basis for future treatments to improve or prevent severe liver diseases.
The Role Of Circadian Rhythm Genes In The Regulation Of Energy Balance And Substrate Metabolism In Muscle And Liver
Funder
National Health and Medical Research Council
Funding Amount
$349,263.00
Summary
Obesity is increasing at an alarming rate worldwide and as the standard of living increases in developing countries such as India and China, the incidence of obesity and its related diseases of diabetes, cardiovascular disease and cancer will become the major health problem of the 21st century. The epidemic of obesity appears to be due to a complex interaction between genetic background and changes in the environment such as reduced physical activity and increased availability and consumption of ....Obesity is increasing at an alarming rate worldwide and as the standard of living increases in developing countries such as India and China, the incidence of obesity and its related diseases of diabetes, cardiovascular disease and cancer will become the major health problem of the 21st century. The epidemic of obesity appears to be due to a complex interaction between genetic background and changes in the environment such as reduced physical activity and increased availability and consumption of high energy food. The accumulation of excess body fat in most individuals is not a precipitous event that occurs over a few days or weeks. Obesity actually occurs insidiously over a period years and is essentially the cumulative result of small differences in daily energy balance. In humans and animals energy balance is subject to diurnal or day-night variations in body temperature, feeding behaviour and physical activity (sleep-wake cycles). Recent research has determined that all tissues in the body have the same genes that regulate circadian (daily) rhythms in the brain. It has also become clear that the expression of these gene cycles over 24 hours in muscle liver and fat tissue the same way that they do in the brain. What is not understood is the extent to which these circadian genes control energy metabolism pathways such as glucose and fat utilisation and storage in liver and muscle. The aim of this grant is to test the effects of changing diet, feeding times and circulating hormones on metabolism and gene expression in muscle and liver to determine the extent to which circadian rhythm genes regulate the normal diurnal metabolism of glucose and fat and whether dysregulation of these systems contributes to metabolic disease.Read moreRead less
IMPAIRED REGULATION OF CYTOCHROMES P450 DURING THE EVOLUTION OF HEPATIC STEATOSIS
Funder
National Health and Medical Research Council
Funding Amount
$186,740.00
Summary
The accumulation of fat in liver is a common problem in early liver injury caused by alcohol, certain drugs and diseases like diabetes. When this occurs the fats can change the amounts of a number of genes and proteins in liver. Cytochrome P450 proteins insert an activated form of oxygen into chemicals, including drugs and fats. In the process, however, some of these activated chemicals can damage surrounding tissues. This project will study the details of how the levels of cytochromes P450 are ....The accumulation of fat in liver is a common problem in early liver injury caused by alcohol, certain drugs and diseases like diabetes. When this occurs the fats can change the amounts of a number of genes and proteins in liver. Cytochrome P450 proteins insert an activated form of oxygen into chemicals, including drugs and fats. In the process, however, some of these activated chemicals can damage surrounding tissues. This project will study the details of how the levels of cytochromes P450 are altered when fat accumulates in liver. The findings may suggest ways in which normal levels of cytochromes P450 can be restored and how to minimise the injurious effects of activated chemicals in liver.Read moreRead less
Post-GWAS Functional Characterisation Of Breast Cancer Susceptibility Loci
Funder
National Health and Medical Research Council
Funding Amount
$764,632.00
Summary
Recent studies have identified regions within the human genome in which DNA sequence variations are associated with an increased risk of breast cancer. Several of these regions do not contain any known genes, suggesting that regulatory DNA sequences are responsible for the associated risk. The aim of this proposal is to identify and characterise these DNA sequences. Understanding how sequences variations in these regions contribute to breast cancer will provide novel avenues for therapy.