Inherited disorders of the blood, such as sickle-cell anaemia and thalassaemia, result from mutations in the genes that produce haemoglobin. Current treatments can partially alleviate some of the debilitating symptoms of these diseases but these treatments have significant side effects, and despite the best efforts of clinicians, many patients succumb to their conditions at an early age. It has been observed that certain individuals exhibit a milder form of the disease, as a consequence of the r ....Inherited disorders of the blood, such as sickle-cell anaemia and thalassaemia, result from mutations in the genes that produce haemoglobin. Current treatments can partially alleviate some of the debilitating symptoms of these diseases but these treatments have significant side effects, and despite the best efforts of clinicians, many patients succumb to their conditions at an early age. It has been observed that certain individuals exhibit a milder form of the disease, as a consequence of the reactivation of their foetal haemoglobin genes, (a distinct set of genes that would have been active in utero but are normally silenced around the time of birth). It is widely accepted that if pharmaceutical means can be found for reactivating the foetal haemoglobin genes then many patients would benefit. The regulation of the foetal globin genes, like most human genes, is complicated and there are few obvious means of increasing their activity. Nevertheless, it is believed that by investigating the molecular mechanisms by which they are controlled it will be possible to devise therapeutic agents that mimic these mechanisms or to develop agents that prevent the shutdown of the foetal genes around birth. To this end we have been working on the molecules that regulate the activity of the haemoglobin genes. We have recently cloned a number of DNA-binding proteins, and their co-factors, that appear to be involved in silencing foetal globin gene expression. This grant proposal is concerned with learning how these new molecules operate to silence gene expression as a first step towards designing agents that will prevent the silencing.Read moreRead less
Genomic Analysis Of The Novel Epigenetic Modifier Smchd1 As A Tumour Suppressor
Funder
National Health and Medical Research Council
Funding Amount
$619,142.00
Summary
Epigenetic modifications are changes made to our DNA that act like punctuation marks in the genome, to instruct the cell when to turn genes on and when to switch them off. Epigenetic control is critical to range of different biological processes, and also goes awry in cancer. We are specifically interested in the role of one new protein involved in epigentic control and characterising its role as a tumour suppressor.
C-JUN TARGETING STRATEGIES AS NOVEL CARDIOPROTECTIVE AGENTS IN ISCHAEMIA-REPERFUSION INJURY
Funder
National Health and Medical Research Council
Funding Amount
$361,148.00
Summary
Acute myocardial infarction (AMI) and its sequelae are an increasing problem in terms of morbidity, mortality and healthcare costs in Australia and the industrialised world; in the USA this is estimated annually at 900,000 and 225,000 patients and US$60 billion, respectively. Current treatment for AMI includes mechanical (percutaneous coronary intervention) or thrombolytic therapy; however, these approaches are directed primarily at epicardial arteries rather than the myocardium and are, therefo ....Acute myocardial infarction (AMI) and its sequelae are an increasing problem in terms of morbidity, mortality and healthcare costs in Australia and the industrialised world; in the USA this is estimated annually at 900,000 and 225,000 patients and US$60 billion, respectively. Current treatment for AMI includes mechanical (percutaneous coronary intervention) or thrombolytic therapy; however, these approaches are directed primarily at epicardial arteries rather than the myocardium and are, therefore, suboptimal. Strategies aimed at directly protecting cardiomyocytes from ischaemia-reperfusion injury, reducing leukocyte recruitment and myocardial cell death, would complement current approaches restoring epicardial artery flow and are keenly sought. This project will demonstrate the capacity of two separate gene-silencing strategies (DNAzymes and siRNA to suppress the expression of the immediate-early gene, c-Jun in cardiomyocytes and reduce infarct size, left ventricular dysfunction, apoptosis, inflammation, production of reactive oxygen species, angiogenesis and fibrosis in the injured rat myocardium. It will also shed light on the molecular mechanisms underlying c-Jun-mediated myocardial inflammation. As such, these studies will provide important proof of principle evidence for these small molecule nucleic acid agents as potential therapeutic tools as cardioprotective agents in ischaemia-reperfusion injury.Read moreRead less
I am a molecular biologist determining the mechanisms of eukaryotic mRNA translation and its regulation by RNA-binding proteins and noncoding RNA. In collaborative work I extend these basic science objectives into the medical research areas of cardiology
Investigation Into The Alternative Splicing Of Steroid Hormone Regulated Genes In Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Steroid hormones have imortant roles in breast tissue growth and differentiation. We have identified several proteins called PRMT6 and CAPER's , that are involved in steroid hormone signaling and control the alternative splicing of RNA, the process in which several different proteins can be produced from a single gene. Our aim is to study these proteins in an effort to understand how they influence alternative splicing and to identify genes they control in relation to breast cancer.
Identifying Target Molecules Regulated By Nuclear Retention In Cancer And Development
Funder
National Health and Medical Research Council
Funding Amount
$267,173.00
Summary
Human DNA contains approximately 30000 genes; only twice as many as worms and flies, ten times as many as bacteria, and fewer than rice. Humans, however have considerably more complexity than these lower organisms. What are the factors responsible for the additional complexity? In the simplest scenario, one gene is transcribed to produce one message (mRNA), which is the blueprint for producing one protein. We now know that there are numerous mechanisms that potentially allow many different prote ....Human DNA contains approximately 30000 genes; only twice as many as worms and flies, ten times as many as bacteria, and fewer than rice. Humans, however have considerably more complexity than these lower organisms. What are the factors responsible for the additional complexity? In the simplest scenario, one gene is transcribed to produce one message (mRNA), which is the blueprint for producing one protein. We now know that there are numerous mechanisms that potentially allow many different proteins to be made from one gene. Also, it is the decisions about which gene will be made ( expressed ) into protein where and when in development, that is critical for our complexity. The control of gene expression is thus fundamental to all cellular processes and many diseases such as cancer and metabolic disorders are associated with some aspect of aberrant gene expression. The production of mRNA from DNA occurs in the human cell nucleus. The nucleus is not simply a bag of DNA, in fact, many important nuclear factors are organised into sub-nuclear bodies . Recently we discovered a novel sub-nuclear body, the paraspeckle and have been identifying its components and their function. Paraspeckles are involved in a previously undiscovered mechanism of the control of gene expression. Here, certain mRNA molecules are trapped in the nucleus until a signal is received from elsewhere in the cell, which causes the mRNA to be released and protein to be made. This Rapid Release Nuclear Retention mechanism effectively allows the quick production of specific proteins to be made on demand. In this project we propose to use cutting edge molecular and cell biology techniques to identify the special mRNA molecules that are trapped in paraspeckles in cancer cells. This will increase our understanding about the molecular details of this process, ultimately leading to potential uses in gene therapy, and should result in the discovery of important targets for cancer treatment.Read moreRead less
The Role Of Food Components In The Modification Of Colorectal Cancer Risk At The Epigenomic Level.
Funder
National Health and Medical Research Council
Funding Amount
$28,609.00
Summary
Colorectal cancer represents a substantial burden to the health system. Primary prevention rather than treatment is more cost effective and can reduce morbidity and mortality. This study program will contribute to the emerging research area of nutrigenomics and nutritional epigenomics, by investigating the interaction between nutrition and gene expression. Such research can assist in establishing a diet which can best help to prevent colorectal cancer, at an individual or population level.
Functional Characterization Of The Regulatory Architecture Of Melanoma-associated Loci
Funder
National Health and Medical Research Council
Funding Amount
$645,663.00
Summary
Melanoma accounts for more than 75% of skin cancer related deaths. In Australia, >10,000 new cases are diagnosed yearly. In this proposal, we will apply novel genetic sequencing technologies developed in our laboratory to examine genomic regions that are associated with melanoma development. By focusing on selected areas, we will obtain a much deeper understanding of how these genes are regulated and find new ways of detecting and treating this disease.