Signalling During Red Blood Cell Invasion By Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$357,414.00
Summary
Malaria is one of the world's most devastating infectious diseases and is caused by a parasite called Plasmodium falciparum. AMA1 is a parasite surface protein crucial for blood cell invasion but how it works is not understood. We are investigating if AMA1 plays a role in helping the parasite sense when it has contacted a blood cell and should invade. Discovering how parasites attach to and invade bloods cells is a priority for the development of anti-parasite drugs and vaccines
ANTIGEN PRESENTATION IN CEREBRAL MALARIA PATHOGENESIS: A ROLE FOR BRAIN MICROVASCULAR ENDOTHELIUM AND MICROPARTICLES
Funder
National Health and Medical Research Council
Funding Amount
$416,012.00
Summary
We want to better understand how lesions occur in the brain during cerebral malaria. We focus our attention on the cells lining the brain blood vessels, called endothelial cells. The originality of this project is to study endothelial cells as immune cells. We already showed that they carry molecules enabling them to activate T lymphocytes and trigger inflammation. Knowing the fine mechanisms by which small brain vessels become damaged will help design better treatments for neuroinflammation.
Is MUC1 A Viable Therapeutic Target For Patients With The Asbestos-induced Tumour Malignant Mesothelioma?
Funder
National Health and Medical Research Council
Funding Amount
$465,068.00
Summary
The deadly asbestos-induced cancer mesothelioma is continuing to kill tens of thousands of people each year. Most patients are diagnosed with advanced disease. We are investigating the use of a specific marker, called MUC1, to improve mesothelioma diagnosis. Improved diagnosis will reduce the time taken to commence treatment. It will also reduce hospital costs and the number of surgical procedures a patients must undergo.
Sorting Nexins And Their Role In Endosomal Trafficking
Funder
National Health and Medical Research Council
Funding Amount
$331,000.00
Summary
Cells are able to internalise molecules via membrane-bound vesicles, a process known as endocytosis. Endocytosis is fundamental for many cellular processes, including receptor signalling, uptake of many essential nutrients and the ability to mount an effective lymphocyte response to foreign antigens. Once internalised, cargo is then sorted to different intracellular destinations of the endosomal transport system. The ultimate destination depends on the particular cargo molecule. The importance o ....Cells are able to internalise molecules via membrane-bound vesicles, a process known as endocytosis. Endocytosis is fundamental for many cellular processes, including receptor signalling, uptake of many essential nutrients and the ability to mount an effective lymphocyte response to foreign antigens. Once internalised, cargo is then sorted to different intracellular destinations of the endosomal transport system. The ultimate destination depends on the particular cargo molecule. The importance of the endosomal transport system is also highlighted by the discovery that many human diseases, including various cancers, lysosomal storage diseases and hypercholesterolemia, are linked to defects in trafficking along the endocytic pathway. Furthermore, a number of viral pathogens, such as HIV, and toxins, such as shiga toxin, exploit the endosomal system to gain entry into a cell. Understanding the molecular details of the sorting events within the endosomal system is necessary to be able to consider therapeutic manipulation of the trafficking of specific cargo molecules. The study seeks to understand the molecular details of the endosomal sorting machinery, knowledge that will underpin future efforts to develop drugs to manipulate movement of proteins within the endosomal system. In the long term, this could allow for the manipulation of a variety of cellular functions including the inhibition of proliferative signals in tumour cells.Read moreRead less
The Molecular Basis Of HLA-linked Drug Hypersensivity Reactions
Funder
National Health and Medical Research Council
Funding Amount
$683,040.00
Summary
Adverse drug reactions are one of the leading causes of death in hospitalised patients. We have discovered a new mechanism that links these reactions to recognition of drug induced changes in immunological self, resulting from interactions of drugs with immune receptors. This project probes the generality of this mechanism by examining the basis of life threatening reactions to drugs used to treat epilepsy (carbamazepine), gout (allopurinol), HIV (Nevirapine) and towards aspirin a commonly used ....Adverse drug reactions are one of the leading causes of death in hospitalised patients. We have discovered a new mechanism that links these reactions to recognition of drug induced changes in immunological self, resulting from interactions of drugs with immune receptors. This project probes the generality of this mechanism by examining the basis of life threatening reactions to drugs used to treat epilepsy (carbamazepine), gout (allopurinol), HIV (Nevirapine) and towards aspirin a commonly used pharmaceutical.Read moreRead less
Shigella Flexneri O Antigen Polysaccharides: Biosynthesis, Function In Virulence, And Interaction With IcsA/VirG
Funder
National Health and Medical Research Council
Funding Amount
$468,055.00
Summary
Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these compo ....Shigella flexneri bacteria cause dysentery in millions of humans each year. The bacterium invades and replicates within the cells of the large intestine. Inside cells, S. flexneri is able to use the host cell's actin-based motility machinery to become motile within the cells, and this can be seen as F-actin comet tails extending from one end of the cell. Bacterial cell surface components residing in the outer membrane are important for the bacterium's ability to cause disease. Two of these components (lipopolysaccharides (LPS) and their polysaccharide chains (O antigens), and IcsA-VirG protein)) are required for initiating actin polymerisation, and mutations affecting synthesis of these components reduce ability to cause disease. In previous studies we have found that O antigen and the synthesis and function of IcsA are interrelated. This project will study how the O antigens are synthesised and their chain length determined by the Wzz protein, and the Wzz structure in relation to its function will also be characterised. The role played by O antigen in intracellular motility will be studied to determine the mechanisms involved. Infection of cells and cell free extracts, antibodies, and an enzyme which specifically degrades the O antigen, will be used to study how O antigen affect the interaction between bacteria with human cell proteins. The relationship between O antigen and IcsA function will be studied using monoclonal antibodies raised to IcsA. The effect of LPS on the outer membrane protease IcsP will be investigated, as will the effect of LPS lipid A mutations on O antigen and virulence. These studies will contribute to a better understanding of the biosynthesis of an ubiquitous bacterial cell surface component (O antigen), its function as a virulence factor in bacterial interactions with host cells. This may lead to novel therapeutic strategies to prevent and control Shigellosis and other bacterial infections.Read moreRead less
Understanding The Complexity Of Antigen Presentation
Funder
National Health and Medical Research Council
Funding Amount
$774,540.00
Summary
I have developed and established the use of mass spectrometry to identify and quantitate ligands of antigen presenting molecules to understand the breadth of immune responses in a variety of human disease states including autoimmunity, cancer, infection and allergy. By embedding the technology in disease focussed research programs I will define the molecular bases of these diseases and the important immunological targets that will provide new avenues for therapeutic development and vaccines.