Heme-oxidised Soluble Guanylyl Cyclase, A Mechanism-based Target For Vascular Diagnostics And Vasoprotective Therapy
Funder
National Health and Medical Research Council
Funding Amount
$524,456.00
Summary
Nitric oxide is produced in the inner lining of blood vessels and maintains blood flow via binding to a specific protein, sGC. In disease, sGC is defective and can be targeted by a novel group of drugs which are more active in diseased versus normal blood vessels. This project will examine the use of these drugs as markers of cardiovascular disease and in the treatment of high cholesterol and may lead to the development of new diagnostic tools and therapies for vascular complications.
Cytokine And Macrophage Determinants Of Pulmonary Inflammation During Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$455,899.00
Summary
Tuberculosis (TB) infects 33% of the world, causing over 2 million deaths per year. TB disease causes damaging lung pathology and new therapies to treat the infection and moderate inflammation are urgently required. TNF is essential for immunity to TB, acting to modulate inflammation. This grant will determine how soluble and membrane- bound TNF regulate the cellular and cytokine control of TB pathology and may lead to new therapies to limit inflammation in TB and other inflammatory diseases.
Microarray-targeted Candidate Gene Approach To Finding Ovarian Cancer Susceptibility Genes
Funder
National Health and Medical Research Council
Funding Amount
$612,933.00
Summary
We propose that subtle, heritable changes in the expression or function of genes that are switched off, or on, early in the development of ovarian tumours, may predispose the individual to ovarian cancer. We will are carry out a large study of the most common subtype of ovarian adenocarcinoma, serous invasive tumors, in order to identify genes that affect a woman's risk of ovarian cancer. Identification of women at elevated risk for ovarian cancer on the basis of their genotype will allow them t ....We propose that subtle, heritable changes in the expression or function of genes that are switched off, or on, early in the development of ovarian tumours, may predispose the individual to ovarian cancer. We will are carry out a large study of the most common subtype of ovarian adenocarcinoma, serous invasive tumors, in order to identify genes that affect a woman's risk of ovarian cancer. Identification of women at elevated risk for ovarian cancer on the basis of their genotype will allow them to be targeted for screening, and for intervention studies, as well as providing fundamental insight into the etiology of ovarian cancer.Read moreRead less
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
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