The Role Of NF-kB Transcription Factors In Regulating T Cell Transcription Networks
Funder
National Health and Medical Research Council
Funding Amount
$534,000.00
Summary
T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. T ....T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. These molecular switches bind groups of proteins known as transcription factors. One family of transcription factors that plays a key role in T cell function is the NF-kB family consisting of five different members, three of which are important in T cell function. Aberrant NF-kB function or expression has been associated with autoimmunity, chronic inflammation and cancer. In addition, NF-kB proteins are key components of transplant rejection. There is enormous interest in using the NF-kB pathway as a therapeutic target for these pathologies. We currently have a detailed knowledge of the biology of these factors through studies of mice lacking specific family members. While we know some of the genes that are switched on by the NF-kB proteins, we currently lack a sufficiently detailed knowledge of NF-kB-regulated genes in order to link the molecular function with the biological outcomes. In order to understand the molecular mechanism of NF-kB function and relate this to the biological outcomes, we need a global view of NF-kB action in the cell. This proposal uses both experimental and computational approaches to decipher the gene expression program controlled by NF-kB proteins in T cells. The T cell transcription networks in which NF-kB proteins participate will also be investigated. The knowledge generated by these experiments will provide a solid basis for designing therapeutic approaches based on the NF-kB pathway.Read moreRead less
Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, ....Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, and how this will change the state of the cell. We propose here to use the new technique of gene arrays to uncover the programs, or groups of genes, which GH regulates to change important cellular processes. When used in conjunction with cells expressing GH receptor mutants which are unable to signal to defined pathways, we will be able to know which functional families genes are regulated, and how they are regulated. This information will enable us to know how GH regulates cell growth and metabolism, and therfore to understand what goes wrong when GH or its mediator, IGF-1 , are abnormal. We can also use this information to validate small molecules designed to mimic GH through activating its receptor, to be certain that they are acting in the same way as GH.Read moreRead less
Molecular Classification Of Carcinoma Of Unknown Primary
Funder
National Health and Medical Research Council
Funding Amount
$418,250.00
Summary
Carcinoma of unknown primary (CUP) is the fourth largest cause of cancer death. The condition has a particularly poor outlook, with a median survival of less than one year. Current methods for diagnosis of CUP include histopathology and sophisticated imaging. These are successful in approximately 40% of cases. Frequently the reason for the poor outcome in this disease is that the 60% of patients with CUP for whom no diagnosis is made do not benefit from chemotherapy specifically designed for a p ....Carcinoma of unknown primary (CUP) is the fourth largest cause of cancer death. The condition has a particularly poor outlook, with a median survival of less than one year. Current methods for diagnosis of CUP include histopathology and sophisticated imaging. These are successful in approximately 40% of cases. Frequently the reason for the poor outcome in this disease is that the 60% of patients with CUP for whom no diagnosis is made do not benefit from chemotherapy specifically designed for a particular tumour origin. These patients receive a less effective, generic, chemotherapy. The aim of this project is to use microarrays to identify the gene expression profile in many known tumours to create a molecular fingerprint of the various tumour types. By comparing the fingerprint from a CUP with the database we should be able to identify the true tumour type in CUP, and allow patients to benefit from more specific chemotherapy.Read moreRead less
Preventing Myocardial Infarction: A Mouse Model Of Atherosclerotic Plaque Instability/rupture As Unique Tool For Establishing Novel Pharmacological Strategies And Targeted Molecular Imaging
Funder
National Health and Medical Research Council
Funding Amount
$586,965.00
Summary
Myocardial infarction strikes without warning and thereby causes death or major disability. It is typically caused by sudden rupture of atherosclerotic plaques and occlusion of coronary arteries. Research on this was hampered by the lack of an animal model of plaque rupture. We have newly established a mouse model, which we will now use to generate novel tools to image and identify plaques that are prone to rupture and to develop novel therapies preventing plaque rupture and myocardial infarctio ....Myocardial infarction strikes without warning and thereby causes death or major disability. It is typically caused by sudden rupture of atherosclerotic plaques and occlusion of coronary arteries. Research on this was hampered by the lack of an animal model of plaque rupture. We have newly established a mouse model, which we will now use to generate novel tools to image and identify plaques that are prone to rupture and to develop novel therapies preventing plaque rupture and myocardial infarction.Read moreRead less
The Use Of Gene Expression Profiles To Predict The Response To Chemoradiotherapy In Patients With Oesophageal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$384,600.00
Summary
One of the most difficult and clinically important questions facing clinicians treating advanced cancer is deciding which patients will, and who will not, benefit from chemotherapy and-or radiotherapy. This is particularly true for clinicians treating locally advanced oesophageal cancer. Oesophageal cancer is a particularly aggressive tumour with a poor prognosis; the majority of patients die within 1 year of diagnosis with only 10% surviving to 5 years. In an attempt to improve outcomes, the us ....One of the most difficult and clinically important questions facing clinicians treating advanced cancer is deciding which patients will, and who will not, benefit from chemotherapy and-or radiotherapy. This is particularly true for clinicians treating locally advanced oesophageal cancer. Oesophageal cancer is a particularly aggressive tumour with a poor prognosis; the majority of patients die within 1 year of diagnosis with only 10% surviving to 5 years. In an attempt to improve outcomes, the use of preoperative (neoadjuvant) combined chemotherapy and radiotherapy as an adjunct to surgery has become common practice. Neoadjuvant therapy has been reported to induce complete regression of the tumour and increased survival times in 20-30% of patients. However, the lack of any apparent clinical benefit for those patients who are poor or non-responders to chemoradiation implies that a large proportion of patients are being exposed to significant toxicity and potential complication for no obvious advantage. In the project outlined in this application, we propose to use cDNA microarrays, a technology that allows the simultaneous assessment of the level of expression of thousands of genes at once, to profile the gene expression patterns of oesophageal tumours. These profiles will then correlated to the patients response to treatment to determine if the gene expression patterns can be used to predict the clinical response to chemoradiotherapy. Success will open the path to the development of a clinically important test that would significantly improve the management of advanced cancer patients by enabling personalised therapy for individual patients. Not only will this allow the selection of the most effective therapy for each patient but it will also free patients from suffering the nasty side effects of treatments that turn out to be of little benefit.Read moreRead less
Radiotherapy (RT) is a curative anti-cancer treatment employed in around half of all cancer sufferers. Very occasionally, a cancer patient will manifest an unexpected adverse reaction to RT and there is strong evidence for a genetic basis to such RT sensitivity. Despite two decades of research, such reactions cannot currently be predicted prior to treatment and their occurrence limits the intensity, and hence cure rates, of RT for the majority of patients. This project will employ cutting edge t ....Radiotherapy (RT) is a curative anti-cancer treatment employed in around half of all cancer sufferers. Very occasionally, a cancer patient will manifest an unexpected adverse reaction to RT and there is strong evidence for a genetic basis to such RT sensitivity. Despite two decades of research, such reactions cannot currently be predicted prior to treatment and their occurrence limits the intensity, and hence cure rates, of RT for the majority of patients. This project will employ cutting edge technology (DNA Chips, or microarrays) to attempt to understand why some patients suffer significant RT side-effects, while the vast majority do not. We have developed a tissue bank of samples from cancer patients who have had adverse RT reactions, and these samples (and samples from unaffected cancer patients) will be examined by microarrays: the activity of thousands of genes will be evaluated in each experiment, and we shall search for patterns of gene activity which track with RT sensitivity. Should we determine a pattern, this pattern will be checked against a larger number of cases and if it accurately predicts RT sensitivity, could lead to the routine testing of cancer patients prior to RT and the individualisation of cancer therapy. In parallel, we will evaluate the tissues of sensitive patients with assays capable of detecting abnormalities in the response to radiation, which may give clues as to an underlying gene fault(s) which might predispose to radiosensitivity in that individual.Read moreRead less
Novel Approaches To The Pathogenesis Of Chronic Hepatitis C Virus Associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated ....The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated. Our preliminary experiments indicated that one particular set of genes related to cell death is upregulated in HCV cirrhosis more than in other kinds of cirrhosis. We propose to pursue the diagnostic-prognostic potential of one of these molecules. Primarily this project will ask what kinds of genes are activated by HCV infection and at various stages of disease progression through to fibrosis and cirrhosis and following liver transplantation to better understand these processes. We believe that this research is likely to lead to a new understanding of hepatitis C associated liver disease that may lead to novel approaches to therapy.Read moreRead less
Progesterone Receptor Action In The Normal Human Breast
Funder
National Health and Medical Research Council
Funding Amount
$360,500.00
Summary
Breast cancer affects 10000 Australian women annually and is a major cause of cancer-related death. The hormone progesterone, which is produced by the ovaries in women, is responsible for many aspects of normal breast development and function. Progesterone is also a major component of hormone replacement therapy (HRT) and oral contraceptives (OCP), which are taken by millions of women worldwide. It has been established that the use of HRT and OCP containing progesterone-like hormones leads to in ....Breast cancer affects 10000 Australian women annually and is a major cause of cancer-related death. The hormone progesterone, which is produced by the ovaries in women, is responsible for many aspects of normal breast development and function. Progesterone is also a major component of hormone replacement therapy (HRT) and oral contraceptives (OCP), which are taken by millions of women worldwide. It has been established that the use of HRT and OCP containing progesterone-like hormones leads to increased breast cancer risk, yet the ways in which this happens are not known. Breast cancer is thought to begin early in a woman's life, with a number of genetic changes that accumulate over a period of many years; the majority of breast malignancies are not diagnosed until after the age of 50. However, there are recent indications that some areas of apparently normal breast have undergone a few genetic changes, even in women with no evidence of malignancy, but there is nothing known about how progesterone may affect these areas and possibly encourage breast cancer development. This project will firstly explore the influence of progesterone on the normal breast, to clarify how this hormone acts in normal cells. We will then investigate the involvement of progesterone in areas of normal breast that have undergone genetic alterations. This will determine whether one way in which progesterone may increase breast cancer risk is by affecting the behaviour of cells with genetic changes to make them more likely to develop further changes and subsequently progress to full cancer development. If women are to continue to derive the benefits of progesterone exposure, there is a compelling need to appreciate how progesterone acts in the normal breast and how it increases breast cancer risk. Achievement of the aims of this project will provide invaluable knowledge and greatly increase our understanding in this area.Read moreRead less
Genetic Programs Regulated By The Nuclear Hormone Receptor, LXR, In Muscle: Control Of Cholesterol And Lipid Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The heightened occurrence of cardiovascular disease has been linked to disorders in lipid metabolism. Obesity, insulin resistance, and atherosclerosis are prevalent diseases associated with these dyslipidemias. Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Disorders of lipid metabolism are associated with cardiovascular disease, insulin resistance-diabetes, obesity and hypertension. Raised levels of serum TGs, and low high density lipoprotein (HDL) cholester ....The heightened occurrence of cardiovascular disease has been linked to disorders in lipid metabolism. Obesity, insulin resistance, and atherosclerosis are prevalent diseases associated with these dyslipidemias. Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Disorders of lipid metabolism are associated with cardiovascular disease, insulin resistance-diabetes, obesity and hypertension. Raised levels of serum TGs, and low high density lipoprotein (HDL) cholesterol levels are characteristic of lipotoxic diseases. HDLs have a defensive role in the prevention of atherogenic dyslipidemia by mediating cholesterol efflux from peripheral tissues through the hormone -dependent ATP-binding cassette (ABC) transporters back to the liver for excretion and elimination. Agents that raise the levels of high density lipoprotein cholesterol (HDLc) through cholesterol efflux provide a pharmaceutical solution for the prevention of hypercholesterolemia, atherogenic and cardiovascular disease. These hormone dependent cholesterol and lipid effluxing proteins are regulated by a protein named LXR. Understanding the functional role of LXR in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body cholesterol homeostasis and lipid metabolism. Furthermore, LXR and LXR target genes that facilitate cholesterol efflux and consequently raise HDLc levels are important pharmaceutical targets. Identification of novel LXR targets in skeletal muscle, which has a significant role in insulin sensitivity and the blood lipid profile provides an additional platform for therapeutic intervention.Read moreRead less
Genetic Programs Induced By The Nuclear Hormone Receptor PPARdelta In Muscle: Control Of Lipid And Energy Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of d ....Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of dyslipidemia by mediating cholesterol efflux from tissues. In contrast, the LDLs accumulate in the arterial wall leading to atherosclerosis. Physiological maintenance of lipid homeostasis requires a dynamic balance between metabolic signalling cascades, diet, lifestyle etc. PPPARs are nuclear hormone receptors that function as fatty acid activated transcription factors that regulate lipid and cholesterol homeostasis. PPARs are bona fide targets for the development of therapeutic compounds useful in the treatment of lipid disorders. PPAR delta is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight. Muscle is a major site of glucose metabolism and, fatty acid oxidation. Furthermore, it is an important regulator of cholesterol homeostasis and HDL levels. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile and lipid metabolism. Understanding the functional role of PPAR delta in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body lipid homeostasis. Understsanding these receptors may provide a pharmaceutical solution for the prevention of hyper-lipidemia--cholesterolemia, and atherogenic disease. Moreover, it may lead to the identification of agents that influence a major mass tissue in terms of lipid absorption, and increased fatty acid oxidation, and consequently normalize the blood lipid profile.Read moreRead less