The Role Of UPF3B And Nonsense Mediated MRNA Decay Surveillance In The Pathology Of Intellectual Disability.
Funder
National Health and Medical Research Council
Funding Amount
$789,954.00
Summary
Proper functioning of the nonsense mediated mRNA decay (NMD or 'mRNA police') is crucial for any cell to ensure normal development and function. When NMD is compromised the outcome is learning and memory problems, autism or schizophrenia. Under this project we study malfunctioning NMD using stem and neuronal cells derived from patients' skin cells. Some of the affected genes might be considered for therapeutic interventions. NMD is relevant to 1000s of human disorders and as such it is of fundam ....Proper functioning of the nonsense mediated mRNA decay (NMD or 'mRNA police') is crucial for any cell to ensure normal development and function. When NMD is compromised the outcome is learning and memory problems, autism or schizophrenia. Under this project we study malfunctioning NMD using stem and neuronal cells derived from patients' skin cells. Some of the affected genes might be considered for therapeutic interventions. NMD is relevant to 1000s of human disorders and as such it is of fundamental importance.Read moreRead less
Gene Profiling To Develop A Neuroprotective Strategy In A Large Animals Model Of Following Ischaemic Stroke.
Funder
National Health and Medical Research Council
Funding Amount
$359,897.00
Summary
Stroke affects 15 million people worldwide each year. At present, the diagnosis and treatment of stroke is not optimal. The use of gene profiling may provide us with information that could allow us to more accurately identify individuals at risk of stroke, predict stroke outcome and effectively treat stroke patients. In addition, by using a targeted approach to therapy we have the potential to reduce brain swelling and improve outcome following stroke with neuroprotective agents.
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
Retinoic Acid Receptor-related Orphan Receptors And The Regulation Of Metabolism:insights Into Diabetes And Obesity
Funder
National Health and Medical Research Council
Funding Amount
$760,799.00
Summary
Nuclear receptors (NRs) function as hormone dependent DNA binding proteins important in sustaining human health, highlighted by the array of medicines that target these proteins for human well being. ROR alpha is one such protein that we have shown regulates fat mass, obesity, and glucose tolerance. Obesity and diabetes are often linked with inflammation. We will examine how ROR controls inflammation during metabolic disease.
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
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
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