Regulation Of Porphyromonas Gingivalis Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
Chronic periodontitis (gum disease) is a chronic inflammatory disease of the supporting tissues of the teeth associated with bacteria that results in the destruction of tooth support and can ultimately lead to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease. The bacterium Porphyromonas gingivalis is recognized as the major causative pathogen in the development of chronic periodontitis. ....Chronic periodontitis (gum disease) is a chronic inflammatory disease of the supporting tissues of the teeth associated with bacteria that results in the destruction of tooth support and can ultimately lead to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease. The bacterium Porphyromonas gingivalis is recognized as the major causative pathogen in the development of chronic periodontitis. This bacterium is part of subgingival dental plaque, a biofilm attached to the surface of the tooth below the gum line, and releases a range of proteins and cytotoxic agents that cause damage to the tooth's supporting tissues both directly and indirectly through the dysregulation of the host's immune response. To cause disease this bacterium must be able to grow as a biofilm and withstand the immune response of the host. Detailed knowledge of how this bacterium is able to establish and proliferate in subgingival plaque, tolerate the oxidative attack and elevated temperatures that are part of the immune response and obtain the essential micronutrient iron will provide new targets for the development of specific inhibitors that may have utility as an adjunctive therapeutic for the control of chronic periodontitis. We will use a state of the art DNA microarray analysis to determine the proteins that regulate genes associated with the virulence of this bacterium. The insights we gain from this study will have broader application for the understanding of human disease that is caused by bacteria that grow as biofilms on various surfaces of the human body.Read moreRead less
Role Of Regulatory Genes In The Control Of Toxin Production In Clostridium Perfringens
Funder
National Health and Medical Research Council
Funding Amount
$495,710.00
Summary
This project investigates how the bacteria responsible for gas gangrene, an often fatal wound infection, control or regulate the expression of genes that encode toxins and other virulence factors. The overall objective is to develop a detailed understanding of the function and biological role of each element in these regulatory systems, thereby making a major contribution to our knowledge of how bacteria control the production of toxic products that are essential for the disease process.
E2F Inhibitors As Anticancer Agents For Squamous Cell Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
Squamous cell carcinoma of the head and neck is one of the six most frequent causes of cancer death worldwide. these tumours are currently treated with surgery, radiotherapy and chemotherapy. Although these treatments are associated with a five year survival rate of between 40% and 60% there is a critical need for more effective and less destructive treatments. In this application we will extend on our earlier work in which we identified the protein E2F1 as being a major contributor to tumour de ....Squamous cell carcinoma of the head and neck is one of the six most frequent causes of cancer death worldwide. these tumours are currently treated with surgery, radiotherapy and chemotherapy. Although these treatments are associated with a five year survival rate of between 40% and 60% there is a critical need for more effective and less destructive treatments. In this application we will extend on our earlier work in which we identified the protein E2F1 as being a major contributor to tumour development. In normal cells, E2F1 is required for the regulated growth of head and neck cells. However, we found that in head and neck tumours, E2F1 is overactive and contributes to the dergulated growth of the tumour. In this project we will test our newly developed inhibitors of E2F1 on various tumour cells derived from head and neck cancers to see how effective they are at stopping tumour cell growth. Furthermore we will test these compounds in animal models of head and neck cancer to determine whether they will be useful therapeutic agents for treatment of human cancer. Early results on tumour cell lines look very promising.Read moreRead less
Regulation Of Toxin Production In Clostridium Difficile
Funder
National Health and Medical Research Council
Funding Amount
$472,169.00
Summary
The research aims to determine how toxin production is controlled in an emerging bacterial pathogen that is a major cause of gastrointestinal infections in hospitals. We will determine the nature of the external signals and the mechanisms by which the bacterium uses those signals to regulate toxin production. These studies will significantly expand our knowledge of how this important bacterium causes disease, a key to developing new methods for the control and treatment of disease.
The Interaction Between CD46 And PSD-95/Dlg-4: Roles In Cell Polarisation And CD46 Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$70,000.00
Summary
Immune defence against pathogens is primarily achieved by the activities of a range of blood cells, including T cells. T cells have specialised functions involving direct killing of the pathogen, and recruitment and activation of other immune cells. Many of these functions require the lymphocyte to become polarised, or asymmetric, in order to concentrate the appropriate cellular machinery towards the site of activity. Examples of polarisation in lymphocytes includes (i) the formation of a single ....Immune defence against pathogens is primarily achieved by the activities of a range of blood cells, including T cells. T cells have specialised functions involving direct killing of the pathogen, and recruitment and activation of other immune cells. Many of these functions require the lymphocyte to become polarised, or asymmetric, in order to concentrate the appropriate cellular machinery towards the site of activity. Examples of polarisation in lymphocytes includes (i) the formation of a single protrusion, or uropod, that forms the basis for cell-cell interactions, (ii) the formation of an immune synapse which allows a T cell to recognise a pathogen, and (iii) the direction of the cellular killing machinery towards the target. The process of cell polarisation is best characterised in neurons and epithelial cells, both of which are asymmetric. In each cell type, a major mechanism of regulating polarisation is the expression and targeting of a family of proteins containing regions called PDZ domains. PDZ domains mediate protein-protein interactions and so allow the assembly of large molecular scaffolds which hold proteins in specific cell sites. The loss of cell polarity in some cells is thought to cause uncontrolled proliferation and tumour progression, and some of the PDZ-containing proteins are tumour suppressors. We have identified a PDZ-containing protein that is polarised in T cells, and have evidence that this protein interacts with and controls the polarisation of a cell surface receptor whose functions include the regulation of T cell function and proliferation. The aim of this proposal is to determine the mechanisms and functional consequences of polarisation of these two proteins in T cells, and to determine whether their interaction or polarisation is important for T cell proliferation.Read moreRead less
Immune defence against pathogens is primarily achieved by the activities of a range of blood cells, including T cells. T cells have specialised functions involving direct killing of the pathogen, and recruitment and activation of other immune cells. Many of these functions require the lymphocyte to become polarised, or asymmetric, in order to concentrate the appropriate cellular machinery towards the site of activity. Examples of polarisation in lymphocytes includes (i) the formation of a single ....Immune defence against pathogens is primarily achieved by the activities of a range of blood cells, including T cells. T cells have specialised functions involving direct killing of the pathogen, and recruitment and activation of other immune cells. Many of these functions require the lymphocyte to become polarised, or asymmetric, in order to concentrate the appropriate cellular machinery towards the site of activity. Examples of polarisation in lymphocytes includes (i) the formation of a single protrusion, or uropod, that forms the basis for cell-cell interactions, (ii) the formation of an immune synapse which allows a T cell to recognise a pathogen, and (iii) the direction of the cellular killing machinery towards the target. The process of cell polarisation is best characterised in neurons and epithelial cells, both of which are asymmetric. In each cell type, a major mechanism of regulating polarisation is the expression and targeting of a family of proteins containing regions called PDZ domains. PDZ domains mediate protein-protein interactions and so allow the assembly of large molecular scaffolds which hold proteins in specific cell sites. The loss of cell polarity in some cells is thought to cause uncontrolled proliferation and tumour progression, and some of the PDZ-containing proteins are tumour suppressors. We have identified a PDZ-containing protein that is polarised in T cells, and have evidence that this protein interacts with and controls the polarisation of a cell surface receptor whose functions include the regulation of T cell function and proliferation. The aim of this proposal is to determine the mechanisms and functional consequences of polarisation of these two proteins in T cells, and to determine whether their interaction or polarisation is important for T cell proliferation.Read moreRead less
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.
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