Understanding The Pharmacoregulation Of The Extracellular Calcium Sensing Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$744,943.00
Summary
Calcium sensing receptors (CaSR) are important regulators of hormone release and modulators of kidney transport, digestion-absorption-satiety and bone mass. In each case, CaSRs adopt a characteristically distinct activating mechanism that we will unravel in detail sufficient for the development of novel chemotherapies e.g., for osteoporosis and obesity. We also anticipate early application of CaSR-based therapies to clinically significant genetic disorders e.g., neonatal hyperparathyroidism.
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
Var Gene Diversity And Naturally Acquired Immunity To Malaria
Funder
National Health and Medical Research Council
Funding Amount
$410,664.00
Summary
In areas where malaria is common, people develop natural immunity to the disease albeit very slowly due to the many parasite strains that circulate. The project will use protein microarrays to investigate the patterns by which antibodies are acquired to the majority of strains. This will reveal how antibodies are acquired with age and which are associated with protection against malaria symptoms. The research aims to identify biomarkers of malaria immunity and may lead to new vaccine candidates.
The Characterisation Of An Essential Regulator Of Pre-mRNA Splicing Required For Germ Cell Function And Male Fertility
Funder
National Health and Medical Research Council
Funding Amount
$1,116,739.00
Summary
The male germ line is a fantastic system within which to define processes of fundamental importance to cell biology and health broadly. Within this grant we will define the role of a poorly described RNA splicing factor in all of stem cell function (spermatogonia), meiosis (spermatocytes) and in the remarkable metamorphosis underlying spermatid maturation. This will be done using a range of phenotypic characterizations, CHIP and RNA Seq technologies and gene sequencing.
Population Genomics Of Plasmodium Falciparum Surface Antigen Genes
Funder
National Health and Medical Research Council
Funding Amount
$385,319.00
Summary
Like most other organisms, each malaria parasite has unique characteristics. A malaria vaccine will need to incorporate these differences to be effective against all parasites in a population. This project will measure the variability and fluctuations of eight of the most promising vaccine targets in a number of natural malaria populations. With this knowledge, a vaccine that is effective against all parasites in the population can be developed and its future success maintained.
Structural Diversity And Evolution Of Variant-specific Surface Proteins In The Protozoan Parasite, Giardia
Funder
National Health and Medical Research Council
Funding Amount
$436,417.00
Summary
Giardia are well-known as a cause of travellers' diarrhoea, but our knowledge about these parasites remains rudimentary. Infections are common in Australia, especially in day-care centres and outback Aboriginal communities. The 1998 Sydney water crisis highlighted the necessity of monitoring reservoirs and reticulated water for contamination by faecal cysts of both human and animal origin. The aim of this project is to learn more about the 'coat' proteins which cover the organisms. These protect ....Giardia are well-known as a cause of travellers' diarrhoea, but our knowledge about these parasites remains rudimentary. Infections are common in Australia, especially in day-care centres and outback Aboriginal communities. The 1998 Sydney water crisis highlighted the necessity of monitoring reservoirs and reticulated water for contamination by faecal cysts of both human and animal origin. The aim of this project is to learn more about the 'coat' proteins which cover the organisms. These protect the parasites against digestion, enabling them to reside indefinitely within the intestine. However, the proteins are also the principal target of host immunity. Analysis of Giardia populations has shown that as many as 150-200 different coat proteins can be made. Although individual cells have coats comprised of only a single protein type, these can 'switch' spontaneously to production of another type - a phenomenon known as 'antigenic variation'. This process occurs slowly but continuously, giving rise to 'variants' which survive successive host responses (directed against each predominant coat type) and occupy the vacancies left by the destruction of their immediate forebears. It is important to gain information about the structural diversity of these variant-specific proteins (VSP), as any 'Giardia' vaccine is likely to require inclusion of each major type. It is also important to elucidate how the 'switching' process occurs, as this may provide clues as to how it might be interrupted. The project addresses both aspects.Read moreRead less