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A Novel Viral Modifier Of TNF Family Receptor Signalling: Elucidation Of Mechanisms Of Action
Funder
National Health and Medical Research Council
Funding Amount
$453,727.00
Summary
Over millions of years, viruses have evolved a great number of strategies to allow them to subvert the effectiveness of the host response. We have discovered that one of these viral strategies seems designed to block the synthesis of an important anti-viral factor, called tumour necrosis factor. In this project, we aim to work out how the viral factor blocks tumour necrosis factor production inside the cell, at the level of the molecules involved. The second aspect of this project concerns the i ....Over millions of years, viruses have evolved a great number of strategies to allow them to subvert the effectiveness of the host response. We have discovered that one of these viral strategies seems designed to block the synthesis of an important anti-viral factor, called tumour necrosis factor. In this project, we aim to work out how the viral factor blocks tumour necrosis factor production inside the cell, at the level of the molecules involved. The second aspect of this project concerns the identification of the types of cells and responses which the viral factor acts upon to manipulate the host response. We reason that this information will improve our understanding of how tumour necrosis factor production is regulated and the significance of this type of response in virus infection and physiology, more generally. The application of this research will be to aid the design of better drugs for the treatment of many conditions where tumour necrosis factor production contributes significantly to pathology, eg rheumatoid arthritis and autoimmunity. In some conditions, it may be a therapeutic advantage to selectively turn on tumour necrosis factor, eg for treatment of infections or cancer.Read moreRead less
Regulation Of TNF Expression In Inflammation And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$728,447.00
Summary
By studying a spontaneous mutation in mice, we have found an error in the TNF gene (a major factor in many inflammatory diseases) that causes severe arthritis, heart valve disease and gut inflammation. We have also identified new regulators of TNF expression, which might be useful therapeutic targets to limit inflammation. We intend to study the role of these regulators in controlling the expression of TNF, and the link between chronic inflammation and the development of cancer.
Fatty Acid Biosynthesis In The Malaria Chloroplast As A Drug Target
Funder
National Health and Medical Research Council
Funding Amount
$131,035.00
Summary
Malarial parasites contain a chloroplast similar to that of plants. We recently found genetic evidence suggesting the malaria chloroplast makes fats in the same way as plant chloroplasts. Additionally, we have found that drugs and herbicides that block plant chloroplast fat production stop growth of malaria cultures. Parasitologists had assumed that malaria was unable to make fats and would scavenge them from its human host so we have probably discovered a new metabolic pathway in these parasite ....Malarial parasites contain a chloroplast similar to that of plants. We recently found genetic evidence suggesting the malaria chloroplast makes fats in the same way as plant chloroplasts. Additionally, we have found that drugs and herbicides that block plant chloroplast fat production stop growth of malaria cultures. Parasitologists had assumed that malaria was unable to make fats and would scavenge them from its human host so we have probably discovered a new metabolic pathway in these parasites. We now propose to prove that the drugs work by blocking essential, chloroplast-based fat production in parasites. This could lead to novel treatment of malaria and related parasites.Read moreRead less
Development Of Recombinant RsolCD39-PSGL As A Novel Therapeutic With Anti-thrombotic And Anti-inflammatory Effects
Funder
National Health and Medical Research Council
Funding Amount
$186,367.00
Summary
Heart disease and stroke are due to a narrowing of arteries followed by occlusion, due a combination of clot formation initiated by platelet clumping, and inflammation surrounding the vessel wall. The currently available drugs are often limited by the adverse reaction of bleeding. We will investigate the efficiency of a new drug to prevent clot formation and inflammation.
The Functional Roles Of ADAMs In The Regulation Of Embryo Implantation.
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
The initiation of pregnancy in humans and rodents hinges upon the ability of the embryo to attach to the wall of the uterus and invade into the uterine tissue. This process of embryo implantation is tightly regulated and depends on the secretion of enzymes and regulators of these enzymes. A newly identified family of enzymes which might be important in this process is the ADAMs family. These enzymes have the potential to facilitate both cell attachment and cell invasion and also to activate othe ....The initiation of pregnancy in humans and rodents hinges upon the ability of the embryo to attach to the wall of the uterus and invade into the uterine tissue. This process of embryo implantation is tightly regulated and depends on the secretion of enzymes and regulators of these enzymes. A newly identified family of enzymes which might be important in this process is the ADAMs family. These enzymes have the potential to facilitate both cell attachment and cell invasion and also to activate other enzymes and growth factors. Recent studies in our laboratory have shown the ADAMs to be expressed both at the most invasive time of implantation and when invasion is being down-regulated. This project will examine the role of the ADAMs in embryo implantation facilitating attachment and invasion into the uterus by acting enzymatically on the uterine tissue and by activating other enzymes. It will also determine the role of ADAMs in down-regulating invasion potentially by activating a growth factor, TNF-alpha. Knowledge of this process and particularly its regulation is important for the treatment of pregnancy associated diseases that arise from improper implantation. These include infertility, placenta accreta, choriocarcinoma, miscarriage and pre-eclampsia. Furthermore, an understanding of the regulation of implantation will contribute to the treatment of other conditions associated with cell invasion such as cancer metastasis.Read moreRead less
GENETIC ANALYSIS OF POLYSACCHARIDE CAPSULE BIOSYNTHESIS AND REGULATION IN STREPTOCOCCUS PNEUMONIAE
Funder
National Health and Medical Research Council
Funding Amount
$377,036.00
Summary
Streptococcus pneumoniae (the pneumococcus) is an important cause of invasive diseases such as pneumonia, meningitis and bacteraemia in humans. Many people carry this organism in the nasopharynx asymptomatically. However, in a small proportion, the organism overcomes host defences and invades the body causing life-threatening disease. An essential virulence factor of the pneumococcus is the polysaccharide capsule which protects it from the immune defences of the host during an infection. Until r ....Streptococcus pneumoniae (the pneumococcus) is an important cause of invasive diseases such as pneumonia, meningitis and bacteraemia in humans. Many people carry this organism in the nasopharynx asymptomatically. However, in a small proportion, the organism overcomes host defences and invades the body causing life-threatening disease. An essential virulence factor of the pneumococcus is the polysaccharide capsule which protects it from the immune defences of the host during an infection. Until recently, very little was known of the pneumococcal genes involved in production of this antigen. This project aims to continue characterization of these genes, and examination of the factors which regulate their expression. This regulatory mechanism may be very important, because production of increased levels of the polysaccharide capsule is believed to be an crucial step in the transition from carriage to invasion. An understanding of the molecular events involved in biosynthesis and regulation of capsule production will improve our understanding of the disease process and identify alternative targets for antimicrobial therapy.Read moreRead less
The prevalence of heart disease and stroke is increasing in the affluent world. These disorders are due to a narrowing of arteries due to clot formation, thereby reducing available blood supply to the heart and brain. Blood vessel occlusion is due a combination of clot formation initiated by platelet clumping, and inflammation surrounding the vessel wall. Drugs that prevent the clumping of platelets on the inner lining of the blood vessels play an important role in the prevention and treatment o ....The prevalence of heart disease and stroke is increasing in the affluent world. These disorders are due to a narrowing of arteries due to clot formation, thereby reducing available blood supply to the heart and brain. Blood vessel occlusion is due a combination of clot formation initiated by platelet clumping, and inflammation surrounding the vessel wall. Drugs that prevent the clumping of platelets on the inner lining of the blood vessels play an important role in the prevention and treatment of heart attack and stroke. The currently available drugs are not universally effective and their use is often limited by adverse reactions. In this submission, we propose to investigate the efficiency of a new drug that will prevent clot formation and will also tackle inflammation. This drug is a derivative of an enzyme that is already present on platelets and cells that line blood vessels. We have modified this enzyme in a manner that will increase the enzyme activity on the surface of platelets and on the cells that line the blood vessel wall. We will thoroughly study this new drug by performing experiments in the laboratory as well as by studying its effect in mice.Read moreRead less