The Function Of BHLH Factors In Adult Haemopoiseis
Funder
National Health and Medical Research Council
Funding Amount
$595,353.00
Summary
Understanding how genes control the behaviour of bone marrow stem cells is currently needed for improving recovery after chemotherapy or bone marrow transplantation and in the future, will aid the application of new stem cell-based therapies for human diseases such as leukaemia. This research will examine how 2 closely related genes control bone marrow stem cell growth and the decision between beocoming a red cell or a white cell.
Spatial And Temporal Aspects Of Epigenetic Remodelling In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$626,707.00
Summary
Epigenetic deregulation occurs commonly in cancer, and can affect not only single genes but can encompass large chromosomal domains, leading to altered expression of oncogenes and tumour suppressor genes, and genomic instability. We will investigate the role of epigenetic remodeling, how spacial reorganisation of the genome, nuclear architecture, chromatin looping and replication timing may affect long range epigenetic deregulation, and ultimately contribute to cancer formation and progression.
Molecular Mechanisms Of Cartilage Degeneration In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$457,517.00
Summary
Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely due to our incomplete understanding of the mo ....Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely due to our incomplete understanding of the molecular changes and pathways involved in both the onset and progression of cartilage breakdown. Powerful new genomic approaches allow simultaneous screening of changes in a broad profile of genes, particulalrly in humans and mice following complete sequencing of their genomes. By applying this new technology in the earliest stages of cartilage degeneration in OA, the role of novel genes and the pathways involved in the onset of this disease process can be discovered. However, to investigate changes at the initiation of disease, tissue from animal rather than human joints must be used due to the difficulty in obtaining pre-symptomatic human cartilage. In order to maximise the number of genes screened, cartilage from a novel surgically induced model of OA in mice will be used in this study. We have developed micro dissection and linear mRNA amplification methods to overcome inherent problems with tissue availability from this small animal species. Successful completion of these studies will for the first time allow identification of the complex changes that occur in early OA. An important and likely outcome of this research will be identification of novel matrix proteins and regulatory molecules that will provide critical information for the development of new diagnostic and therapeutic approaches to OA.Read moreRead less
Restoration Of P53 Activity In Tumours: A New Approach Involving The P53 Coactivator ANKRD11.
Funder
National Health and Medical Research Council
Funding Amount
$465,990.00
Summary
p53 is an important protein that functions as the body�s defence mechanism against cancer. Mutation of p53 is observed in over half of all tumours. Not only do these cancer mutations abolish the ability of p53 to protect against cancer, but it also endows the tumours with an ability to spread throughout the body, or metastasize. In this research project, we will identify and develop targets that will not only prevent the spread of new tumours, but it will also re-activate the anti-cancer functio ....p53 is an important protein that functions as the body�s defence mechanism against cancer. Mutation of p53 is observed in over half of all tumours. Not only do these cancer mutations abolish the ability of p53 to protect against cancer, but it also endows the tumours with an ability to spread throughout the body, or metastasize. In this research project, we will identify and develop targets that will not only prevent the spread of new tumours, but it will also re-activate the anti-cancer function in mutant p53 leading to tumour regression.Read moreRead less
Molecular Mechanisms For The Cell-type Specific Regulation Of The Tissue-type Plasminogen Activator Gene
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will ....Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will address the mechanisms underlying the cell-type specific regulation of the t-PA gene. Endothelial cells, fibroblasts and neuronal cell cultures will be used to study the regulation of t-PA expression. Information gained will not only add to the understanding of the broader field of gene regulation, but may also provide clues to manipulate the expression of the t-PA gene in different cells.Read moreRead less
Role Of NF-kB Recruited SWI/SNF Chromatin Remodeling Complexes In Inducible Gene Expression In T Cells
Funder
National Health and Medical Research Council
Funding Amount
$243,500.00
Summary
The immune system consists of a group of cell types, including T cells, which are capable of recognising foreign agents and eradicating them from the body. T cells are activated by foreign antigen and respond by producing an array of soluble factors including cytokines, which act as communicators between cells. The correct expression of these factors is critical for the maintenance and function of the immune system, and is therefore tightly regulated. The genes encoding these factors are general ....The immune system consists of a group of cell types, including T cells, which are capable of recognising foreign agents and eradicating them from the body. T cells are activated by foreign antigen and respond by producing an array of soluble factors including cytokines, which act as communicators between cells. The correct expression of these factors is critical for the maintenance and function of the immune system, and is therefore tightly regulated. The genes encoding these factors are generally maintained in an 'inactive' state but are switched on rapidly when required. Within the cell, genes or DNA are found wrapped up in a complex protein structure called chromatin which plays an important role in regulating gene expression. Chromatin forms a barrier to active gene expression which must be overcome before the gene can be switched on. There are protein complexes within the cell that are able to alter or remodel chromatin structure from an 'inactive' to an 'active' state. We are investigating one of these chromatin remodeling complexes to determine which genes it is able to switch on and how it targets these particular genes. Aberrant gene expression within T cells contributes to a range of diseases including certain leukemias and inflammatory conditions such as asthma and rheumatoid arthritis. Understanding the events and protein complexes involved in switching on specific genes in T cells will potentially identify molecules which can be targeted in an effort to control inappropriate gene expression in these disease states.Read moreRead less
Role Of Immediate Early Gene Induction And AP-1 Activation In HDAC Inhibitor Induced Apoptosis.
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Histone deacetylase inhibitors (HDACi) are a novel class of anti-tumor agents, recently approved for the treatment of cutaneous T-cell lymphoma. The goal of this study is to improve our understanding of how this class of drug induces tumor cell death. These studies are designed to provide insight into which patients are most likely to benefit from treatment with these agents. Second, they will provide direction into how the therapeutic efficacy of HDACi may be enhanced, through combination with ....Histone deacetylase inhibitors (HDACi) are a novel class of anti-tumor agents, recently approved for the treatment of cutaneous T-cell lymphoma. The goal of this study is to improve our understanding of how this class of drug induces tumor cell death. These studies are designed to provide insight into which patients are most likely to benefit from treatment with these agents. Second, they will provide direction into how the therapeutic efficacy of HDACi may be enhanced, through combination with other existing therapeutics.Read moreRead less
A Role For Epigenetic Modifiers In Maintaining Chromosome Integrity During Passage Through The Male Gamete In The Mouse.
Funder
National Health and Medical Research Council
Funding Amount
$390,541.00
Summary
There is a high level of infertility in the human population, the majority of which remains unexplained. 15% of married couples in the United States are affected by infertility and it is estimated that the male partner is responsible for half of this. Some of this infertility is familial indicating an underlying genetic cause. An increased understanding of the underlying genes involved, should lead to improvements in treatment. The mouse, with its ability to produce large numbers of offspring an ....There is a high level of infertility in the human population, the majority of which remains unexplained. 15% of married couples in the United States are affected by infertility and it is estimated that the male partner is responsible for half of this. Some of this infertility is familial indicating an underlying genetic cause. An increased understanding of the underlying genes involved, should lead to improvements in treatment. The mouse, with its ability to produce large numbers of offspring and its ability to be genetically modified, provides an excellent model system for studying the genetic contribution to reproductive fitness. The studies outlined in this application aim to determine whether a group of genes, previously identified as a result of their effects on epigenetic gene silencing, are also involved in reproductive fitness in the mouse. Our hypothesis is that these genes encode proteins required for normal pairing and segregation of chromosomes during male gametogenesis. While none of the experiments described here involve studies on humans, the genes identified are likely to have human homologues. It will, then, be relatively simple to discover whether infertile men carry mutations in these genes. Assisted reproductive technologies (ART) now accounts for between 1% and 3% of annual births in many western countries and IVF services continue to grow. While these procedures provide an effective treatment for many infertile couples, they promote the transmission of any underlying genetic defects to the next generation. These genetic defects, therefore, need to be identified and understood. Recently it has been reported that the frequency of some rare diseases are, indeed, higher in ART offspring. Furthermore, if our hypothesis is correct and some of the genes involved are critical for chromosome integrity, then mutations in these genes may also increase the risk of cancer later in life.Read moreRead less
Identification Of Novel Mechanisms Governing Stage-specific Regulation Of The Human Globin Genes
Funder
National Health and Medical Research Council
Funding Amount
$577,889.00
Summary
Hemoglobin is the major protein in red blood cells and is essential for the transport of oxygen from the lungs to the tissues. The disorders of hemoglobin production are the commonest genetic diseases world-wide. These diseases can be markedly improved with elevation of the form of hemoglobin produced by the developing embryo, embryonic hemoglobin. We have identified a key factor important for fetal gene expression. Our goal is to translate these findings into therapies for the globin disorders.
Transcriptional Regulation Of The Complement Receptor 2 Gene (CR2/CD21) During B Cell Lineage Committment
Funder
National Health and Medical Research Council
Funding Amount
$466,500.00
Summary
The complement system is a very important pathway within the human immune system. One of the receptors within this system is complement receptor 2 or CR2. CR2 has not only been shown to be important within the inflammatory response and defence against microbes but is also important in normal generation of a B cell immune response . B cells not only produce antibodies against foreign organisms but in some cases dysfunction of the B cell can bring about autoimmunity by production of antibodies aga ....The complement system is a very important pathway within the human immune system. One of the receptors within this system is complement receptor 2 or CR2. CR2 has not only been shown to be important within the inflammatory response and defence against microbes but is also important in normal generation of a B cell immune response . B cells not only produce antibodies against foreign organisms but in some cases dysfunction of the B cell can bring about autoimmunity by production of antibodies against self tissues and cells . How the CR2 gene turns on expression on different cells within the immune system is complex. The amount of receptor on the surface of antibody producing B cells has important implications to B cell biology. As CR2 expression is turned on at an important point within the antibody producing B cell and the levels of this receptor can influence B cell function, understanding how this gene is regulated is important.Read moreRead less