Making Signalling Through The Tumour Necrosis Factor Receptors Selective For Promoting Neutrophil Antimicrobial Activity
Funder
National Health and Medical Research Council
Funding Amount
$196,312.00
Summary
It is evident to the professional and general community that antibiotic and drug resistance displayed by bacteria is a continuing and growing problem in the treatment of infection with potentially casastrophic effect on the health of our community. This concern is only partly reduced by our potential to develop new antimicrobial agents and vaccines. If we were able to use immunomodulators in a relatively safe and appropriate manner to target and enhance the antimicrobial power of specific compon ....It is evident to the professional and general community that antibiotic and drug resistance displayed by bacteria is a continuing and growing problem in the treatment of infection with potentially casastrophic effect on the health of our community. This concern is only partly reduced by our potential to develop new antimicrobial agents and vaccines. If we were able to use immunomodulators in a relatively safe and appropriate manner to target and enhance the antimicrobial power of specific components of the immune system then this could be exploited in the treatment of infection. While body proteins formed (cytokines) which modify the behaviour of the immune system are being used as pharmaceuticals, their toxic side effects are problematic to the patient. Our project focusses on one of the cytokines, tumor necrosis factor (TNF), which increases the antimicrobial activity of phagocytic cells but in addition can have quite devastating effects on other tissues in the body. This is because when TNF binds to its receptor on cells and tissues it elicits a multitude of signals inside the cell which can also precipitate illness. The purpose of our investigations is to identify which signals are responsible for increasing resistance against infection and which are not. With this information we will then see if it is feasible to selectively stimulate this signal from outside the cell since this has a better chance of succeeding as a pharmaceutical. This task is likely to be achievable since our research team has made some unique observations about TNF signalling characteristics and we have developed a peptide TNF mimetic which shows only the characteristics of increasing antimicrobial activity.Read moreRead less
Studies On Mechanisms Of Vesicular Trafficking And Catalysis For The Menkes (MNK) Copper-transporting P-type ATPase
Funder
National Health and Medical Research Council
Funding Amount
$363,757.00
Summary
Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic Ofree radicalsO. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and Omad cowO disease. Menkes disease is an inherited and usually lethal cop ....Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic Ofree radicalsO. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and Omad cowO disease. Menkes disease is an inherited and usually lethal copper deficiency disorder in humans, and the diverse and detrimental symptoms of this disease related to organs and tissues described above is a stark indicator of the essentiality of copper. We have carried out extensive research on Menkes disease and in particular the Menkes protein which in normal individuals plays a major role in maintaining the copper balance in cells, i.e. enough Cu to satisfy nutritional needs of cells but not too much which causes toxicity. The normal Menkes protein catalyses the transport of Cu across membranes of cells to the areas where it is needed by copper-dependent enzymes which themselves catalyse important chemical reactions. The normal Menkes protein functions as a molecular pump. We have discovered that this protein can OsenseO Cu concentrations in the cell and when these reach potentially toxic levels it can move (traffick) via small vesicles to the plasma membrane which surrounds cells. There it pumps the excess Cu out of the cell and returns to its original location. Our studies are directed to understanding the molecular mechanisms which permit this remarkable protein to achieve a copper balance in living cells. The findings will be of major significance in understanding and treating acquired and inherited diseases involving copper deficiency or copper toxicity.Read moreRead less
PrtFII, A Streptococcus Pyogenes Fibronectin Binding Protein, And Invasive Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$296,540.00
Summary
Our recent work revealed that, in the Aboriginal population, young age is a risk factor for severe invasive diseases caused by group A streptococcus. For group A streptococcus infection to occur, bacterial attachment is the first step. The bacterium attaches to host cells through interactions involving host fibronectin and the pathogen's fibronectin-binding proteins. We have found that streptococcal strains from severe disease cases are more likely to have the gene for PrtFII, a fibronectin bind ....Our recent work revealed that, in the Aboriginal population, young age is a risk factor for severe invasive diseases caused by group A streptococcus. For group A streptococcus infection to occur, bacterial attachment is the first step. The bacterium attaches to host cells through interactions involving host fibronectin and the pathogen's fibronectin-binding proteins. We have found that streptococcal strains from severe disease cases are more likely to have the gene for PrtFII, a fibronectin binding protein, than those from uncomplicated skin sores. In this application we propose to extend this observation and compare biochemical properties of PrtFII from strains belonging to the above two sets of collections. We hypothesise that PrtFII from invasive strains bind to fibronectin more tightly than the proteins from strains that cause uncomplicated infection. We also will test whether sera from invasive disease cases have lower titre of antibodies to the conserved region of PrtFII than sera from uncomplicated cases. A streptococcal vaccine by necessity has to be a multi-component vaccine to cover a wide spectrum of diseases and epidemiological differences. The study proposed here may provide a basis to argue whether or not to include PrtFII in such a multi-component vaccine.Read moreRead less
In Vivo And In Vitro Studies Of The Human -308 TNF Promoter Polymorphism.
Funder
National Health and Medical Research Council
Funding Amount
$232,131.00
Summary
The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarif ....The identification of genetic variation in region of the DNA that controls expression of the inflammatory cytokine Tumour Necrosis Factor (TNF) and its association with a number of autoimmune and inflammatory diseases, has led to speculation that this genetic difference may play a role in predisposing some people to these diseases. We have isolated an activity, TPF1, that may regulate expression through interaction with this DNA control region. During the tenure of this grant we intend to clarify some of these questions, we will generate genetically modified mice that have either of the two genetic forms of the human TNF promoter. These mice will be compared in two models of associated disease, murine Lupus and cerebral malaria. We will also characterise the interactions of TPF1 with other components of the TNF control region. An understanding of the role of TPF1 in controlling TNF expression and an appreciation of the cell types that are able to express the phenotype, will allow the development of more subtle, cell specific strategies to modulate the activity of TNF without completely abolishing expression and may lead to better preventative and therapeutic strategies.Read moreRead less
Designer RNA-binding Proteins For Research And Therapeutic Purposes
Funder
National Health and Medical Research Council
Funding Amount
$557,480.00
Summary
It has become clear recently that ribonucleic acids play many roles in the switching on and off of genes in humans and other organisms. These molecules play roles in a number of diseases, including HIV-AIDS, hepatitis, and a large number of inherited disorders. We propose to build a library of protein molecules that can bind specifically to a wide range of RNA targets and modulate their function. These molecules have the capacity to act as therapeutics for a wide range of diseases.
The Transcription Factors C-Rel And RelA Serve Distinct Roles In The Devlopment And Function Of CD4 Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$492,991.00
Summary
An unfortunate consequence of immune function is that occasionally rogue immune cells are produced that attack the host and lead to the development of so-called autoimmune diseases such as arthritis. Normally a white blood cell called a regulatory T cell suppresses these self reactive immune cells. We have identified factors that govern genetic programs in regulatory T cells. Understanding how these factors work should permit the development of new strategies to combat autoimmune diseases.
Lipocalin 2 In Host Defence Of The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$575,014.00
Summary
Lipocalin 2 is a protein that is involved in protection of the host organism against bacterial infections. We have found that high levels of lipocalin 2 are produced by a variety of cells in the brain in response to not only bacterial products but also to infection with West Nile virus (WNV). WNV is a dangerous virus known to cause lethal encephalitis. This project will determine the role of lipocalin 2 in the defence of the host against WNV encephalitis.
The Role Of IL-18 In Proliferative And Crescentic Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$56,177.00
Summary
Inflammation of the small filters with the kidneys, known as glomerulonephritis, is the commonest cause of kidney failure in Australia. People whose kidneys have failed need either kidney dialysis or a kidney transplant. Our understanding of the immune events that cause glomerulonephritis is patchy. However, it is known that T cells are the directors of immune responses in the body and direct the immune response in glomerulonephritis. Chemical messengers known as cytokines direct the way T cells ....Inflammation of the small filters with the kidneys, known as glomerulonephritis, is the commonest cause of kidney failure in Australia. People whose kidneys have failed need either kidney dialysis or a kidney transplant. Our understanding of the immune events that cause glomerulonephritis is patchy. However, it is known that T cells are the directors of immune responses in the body and direct the immune response in glomerulonephritis. Chemical messengers known as cytokines direct the way T cells behave. One of these cytokines, known as interleukin-18, has been shown to stimulate T cells and other immune cells to induce inflammation that is helpful when the body is fighting infection but is harmful in immune diseases. This project will determine the role of interleukin-18 in glomerulonephritis by studying the way it talks to T cells and the mechanisms by which it incites inflammation in the kidney. Mice with glomerulonephritis will be treated by blocking the actions of interleukin-18 to discover whether interleukin-18 produced by the animal is important in kidney damage induced by glomerulonephritis, to understand the way in which this cytokine works and to assess whether blocking interleukin-18 could be a useful treatment for glomerulonephritis in humans. Current treatments for glomerulonephritis are often ineffective and have unwanted side effects. Knowledge of the way interleukin-18 participates in the immune response in glomerulonephritis may lead directly or indirectly to more effective and more targeted treatments for different forms of glomerulonephritis.Read moreRead less
Identifying New Therapeutic Targets For Preventing The Induction And Progression Of COPD
Funder
National Health and Medical Research Council
Funding Amount
$649,314.00
Summary
Smoking leads to lung inflammation that causes emphysema, which is a major health problem in Australia. Once induced there is a progressive decline in health, which continues even after stopping smoking. There are no treatments that halt this decline. Recently small genes have been discovered that control inflammation. We may be able to control these small genes and stop the induction and progression of emphysema. This project may lead to a completely new way of preventing and treating emphysema ....Smoking leads to lung inflammation that causes emphysema, which is a major health problem in Australia. Once induced there is a progressive decline in health, which continues even after stopping smoking. There are no treatments that halt this decline. Recently small genes have been discovered that control inflammation. We may be able to control these small genes and stop the induction and progression of emphysema. This project may lead to a completely new way of preventing and treating emphysema.Read moreRead less
Polyunsaturated Fatty Acids Mimetics With Anti-inflammatory Properties
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Autoimmune diseases are responsible for a high incidence of morbidity and mortality in our community. Immunosuppressive drugs-anti-inflammatory agents have played important roles in treatment of these diseases as well as in helping to prevent rejection of transplanted tissues-organs. There is an ongoing search by the medical community for better immunosuppressive drugs and agents for use for these purposes. Based on studies conducted in the last few years, we have partially identified structural ....Autoimmune diseases are responsible for a high incidence of morbidity and mortality in our community. Immunosuppressive drugs-anti-inflammatory agents have played important roles in treatment of these diseases as well as in helping to prevent rejection of transplanted tissues-organs. There is an ongoing search by the medical community for better immunosuppressive drugs and agents for use for these purposes. Based on studies conducted in the last few years, we have partially identified structural elements on polyunsatrated fatty acids (PUFA) which are responsible for specific biological functions. Using this information, we have synthesized a large panel of previously unavailable PUFA which we can use to target T lymphocytes and drive the biological activity of these compounds, preferentially towards immunosuppression. By conducting the research outlined in this project, we are likely to either identify a lead immunosuppressive compound or generate new information for further synthesis of PUFA-based compounds for further examination as potential immunosuppressive agents.Read moreRead less