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
A Structural And Functional Basis For The Regulation Of Gene Expression By Nuclear Retention Of RNA
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
The nuclear retention mechanism is a novel way used by cells to control which genes are made into proteins - a fundamental process for all diseases, particularly cancers. This project will employ cutting edge structural and proteomic techniques to determine the molecular details underpinning nuclear retention. These insights will be important for the development of new tissue-restricted gene therapy applications and drugs targeting the cancers that rely on this mechanism.
Understanding The Physiological Role Of COUP-TF Orphan Nuclear Receptors In Skeletal Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$454,923.00
Summary
COUP-TF is a protein expressed in skeletal muscle, a tissue that accounts for ~40% of the body mass and energy expenditure, and is a major site of nutrient metabolism. COUP-TF is a member of the nuclear hormone receptor (NR) superfamily. These proteins respond to physiological signals, and are targets of pharmaceuticals for the treatment of inflammation, metabolic and endorcrine disorders. Our project is directed toward understanding the role of COUP-TF in the context of metabolism and obesity.
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
Transcriptome Profiling Of The Human Pathogen Schistosoma Japonicum
Funder
National Health and Medical Research Council
Funding Amount
$257,560.00
Summary
The parasitic disease, schistosomiasis, caused by human bloodflukes of the genus Schistosoma, is a major public health issue in Africa, Latin America and South East Asia. Current control methods are far from ideal, and a comprehensive understanding of the genetic mechanisms which allow schistosomes to grow, develop and survive within their hosts affords the best prospect for identifying new drug and vaccine targets. Microarray technology allows simultaneous monitoring of thousands of different g ....The parasitic disease, schistosomiasis, caused by human bloodflukes of the genus Schistosoma, is a major public health issue in Africa, Latin America and South East Asia. Current control methods are far from ideal, and a comprehensive understanding of the genetic mechanisms which allow schistosomes to grow, develop and survive within their hosts affords the best prospect for identifying new drug and vaccine targets. Microarray technology allows simultaneous monitoring of thousands of different genes, and to determine where and when they are active, thus placing the mass of data generated by genome sequencing programs into a biological and functional context. Microarrays provide a unique, cutting-edge, tool for investigating schistosome biology. We have fabricated a microarray representing some 20,000 schistosome genes. We will use this resource to perform large scale monitoring of schistosome gene expression during the parasite's complex life cycle, targetting the regionally important Asian schistosome, Schistosoma japonicum, for study. This will provide the single largest insight into the genetic changes that occur during schistosome development, will greatly further our understanding of the adaptations needed for the growth, development and survival of the parasite, and will identify genes involved in key biological processes, all of which may be exploitable for future interventions and treatments.Read moreRead less
Functional Significance Of ATM-dependent Phosphorylation Of Mre11
Funder
National Health and Medical Research Council
Funding Amount
$211,500.00
Summary
The aim of the project is to investigate the response of human cells to radiation damage to DNA. Radiation causes double strand breaks in DNA which are responsible for its carcinogenic activity. Several rare syndromes have been described where there is a hypersensitivity to radiation and an increased risk of developing cancer. Cells from these patients have provided a useful means of understanding the basis of sensitivity to radiation and how this may be linked to diseases such as cancer. The in ....The aim of the project is to investigate the response of human cells to radiation damage to DNA. Radiation causes double strand breaks in DNA which are responsible for its carcinogenic activity. Several rare syndromes have been described where there is a hypersensitivity to radiation and an increased risk of developing cancer. Cells from these patients have provided a useful means of understanding the basis of sensitivity to radiation and how this may be linked to diseases such as cancer. The intention here is to investigate some of the normal mechanisms of cellular response to radiation and determine why they are deficient in cells from individuals with these rare syndromes. We will focus on a protein, ATM, which is activated by radiation and on one of its substrates Mre11. Both molecules are involved in sensing and transmitting signals from DNA to cell cycle checkpoints. The expected outcome of this study is a greater understanding of the intricate set of signaling pathways that are activated in response to radiation damage. In addition it is expected that a detailed knowledge of these pathways and what goes wrong in specific disease states will be of assistance in understanding risk of developing cancer. Finally this information will also be useful in the design of novel compounds for the prevention and-or treatment of cancer.Read moreRead less
MicroRNA Networks That Safeguard The Functional Program Of Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$457,941.00
Summary
A newly discovered group of molecules termed microRNAs are thought to function as rheostats for the activity of genes. We have shown that these molecules are critical for the function of an immune cell type termed regulatory T cells. Without these cells, the immune system is unable to prevent uncontrolled and destructive inflammation. This proposal aims to utilize diverse technologies to uncover the precise molecular mechanisms by which microRNAs safeguard the function of regulatory T cells.
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