Regulation of local lymphocyte trafficking and its role during infection. The study of early immune responses will contribute to the development of better vaccination strategies. In particular it will contribute by helping to understand the essential differences between reactogenicity and immunogenicity and how this relates to adjuvants. Using this understanding it will be possible to develop novel adjuvants that induce appropriate immunity with minimal side effects.
Poly(amino acids) as immune stimulators. This project aims to develop nanoparticles built from natural hydrophobic amino acids as an immune stimulatory delivery system for peptide antigens. Currently available immune stimulants (adjuvants) are often toxic and/or are poorly chemically defined fragments of bacteria or toxins and vary from batch-to-batch. New adjuvants are in high demand; especially to facilitate the use of optimal, but weakly immunogenic, peptide antigens. It is expected that the ....Poly(amino acids) as immune stimulators. This project aims to develop nanoparticles built from natural hydrophobic amino acids as an immune stimulatory delivery system for peptide antigens. Currently available immune stimulants (adjuvants) are often toxic and/or are poorly chemically defined fragments of bacteria or toxins and vary from batch-to-batch. New adjuvants are in high demand; especially to facilitate the use of optimal, but weakly immunogenic, peptide antigens. It is expected that the proposed project will develop a novel efficient, safe and notably biodegradable self-adjuvanting delivery system that can be fully customised to match an antigen of choice. This foundational research should provide important advances for commercial immune stimulatory applications.Read moreRead less
Mechanistic basis of a reproductive lesion in transforming growth factor beta-1 (TGFb1) null mutant mice. Null mutation in the gene encoding the cytokine transforming growth factor beta-1 (TGFb1) causes infertility in male and female mice. In recent experiments we have found that TGFb1 deficiency is associated with impaired ovarian and testicular steroidogenesis, arrested development of pre-implantation embryos and disrupted mammary gland morphogenesis. The aims of the current project are to un ....Mechanistic basis of a reproductive lesion in transforming growth factor beta-1 (TGFb1) null mutant mice. Null mutation in the gene encoding the cytokine transforming growth factor beta-1 (TGFb1) causes infertility in male and female mice. In recent experiments we have found that TGFb1 deficiency is associated with impaired ovarian and testicular steroidogenesis, arrested development of pre-implantation embryos and disrupted mammary gland morphogenesis. The aims of the current project are to unravel the mechanistic basis of the reproductive lesion in TGFb1 null mutant mice and to determine the effect of exogenous systemic delivery of TGFb1 in alleviating this lesion. It is expected that the project will provide new insight into key roles for TGFb1 in governing male and female fertility, and shed light on the prospects for exogenous supplementation of TGFb1 for improving reproductive performance in wild-type animals. This knowledge has potentially important applications in the livestock breeding industry, in devising novel contraceptive vaccine strategies, in the human pharmaceutical industry, and in devising novel contraceptive vaccine strategies.Read moreRead less
Malarial parasite surface proteins: structure and interactions of key merozoite antigens. Malaria remains one the most lethal infectious diseases in the world today, being directly responsible for around 2 million deaths annually, many in children under 5 years of age. Related parasitic diseases affect livestock in malaria-endemic regions and more broadly. There is an urgent need for an improved understanding of how these parasites invade target red blood cells. Knowing the structures of key pro ....Malarial parasite surface proteins: structure and interactions of key merozoite antigens. Malaria remains one the most lethal infectious diseases in the world today, being directly responsible for around 2 million deaths annually, many in children under 5 years of age. Related parasitic diseases affect livestock in malaria-endemic regions and more broadly. There is an urgent need for an improved understanding of how these parasites invade target red blood cells. Knowing the structures of key proteins on the parasite cell surface will provide a deeper understanding of host-parasite interactions, as well as a basis for the design of vaccines or drugs that interfere with parasite invasion of host red blood cells. Read moreRead less
Chemical tools for the study of mycobacterial glycolipid biosynthesis. Mycobacteria are responsible for human morbidity and mortality on a immense scale. The cell wall structure of these bacteria is extremely complex and offers many novel therapeutic opportunities. In this proposal we will use a synergetic interplay of chemistry, biochemistry and microbiology to study the biosynthesis of essential cell wall molecules conserved across all mycobacteria, the phosphatidylinositol mannosides. Substr ....Chemical tools for the study of mycobacterial glycolipid biosynthesis. Mycobacteria are responsible for human morbidity and mortality on a immense scale. The cell wall structure of these bacteria is extremely complex and offers many novel therapeutic opportunities. In this proposal we will use a synergetic interplay of chemistry, biochemistry and microbiology to study the biosynthesis of essential cell wall molecules conserved across all mycobacteria, the phosphatidylinositol mannosides. Substrates and inhibitors will be prepared and studied using novel biochemical and microbiological methods. This project will enhance our understanding of cell wall synthesis in mycobacteria and will lay the ground work for the discovery of novel antibiotics.Read moreRead less
Dissociation of a Tetrameric Enzyme with Interface-Targeted Peptides. With antibiotic resistance on the rise, there is an urgent need to develop new antibiotics and an equally urgent need to characterise new antibiotic targets. One such target is dihydrodipicolinate synthase (DHDPS) which catalyses the critical step in lysine and cell wall biosynthesis in bacteria. This proposal aims to generate new drugs targeting DHDPS for effective and rapid treatment of bacterial infections, including gastro ....Dissociation of a Tetrameric Enzyme with Interface-Targeted Peptides. With antibiotic resistance on the rise, there is an urgent need to develop new antibiotics and an equally urgent need to characterise new antibiotic targets. One such target is dihydrodipicolinate synthase (DHDPS) which catalyses the critical step in lysine and cell wall biosynthesis in bacteria. This proposal aims to generate new drugs targeting DHDPS for effective and rapid treatment of bacterial infections, including gastroenteritis. Recent statistics show that over 5 million Australians suffer from gastroenteritis each year and hospitalisation for this infection is nearly seven times higher for indigenous than non-indigenous children. Accordingly, this research has the potential to assure a healthier future for millions of Australians.Read moreRead less
Cell biology of gastric acid secretion. This research will result in a better understanding of the membrane structures in cells. In turn, this information could be exploited to manipulate ion transport, uptake, secretion of biological molecules, signal transduction events and the delivery and uptake of drugs in a number of disease situations thus leading to more effective therapies.
Furthermore, this work will utilise and develop state-of-the-art technologies, contributing to national competiti ....Cell biology of gastric acid secretion. This research will result in a better understanding of the membrane structures in cells. In turn, this information could be exploited to manipulate ion transport, uptake, secretion of biological molecules, signal transduction events and the delivery and uptake of drugs in a number of disease situations thus leading to more effective therapies.
Furthermore, this work will utilise and develop state-of-the-art technologies, contributing to national competitiveness in this area. A number of students and postdoctoral fellows will be trained as a consequence of working on this project
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Multifunctional biodegradable nanoparticles for enhanced DNA vaccine delivery. DNA vaccine, which shows better immunological and economic merits than conventional vaccines, suffers clinical failure due to the difficulty of delivering intact DNA molecules to relevant cells. This project seeks to develop smart polymer nanospheres to protect the DNA molecules from premature degradation in order to improve its efficacy.
Noncanonical epitope recognition by CD8+ T lymphocytes. This proposed research program will provide significant fundamental insight in the areas of immunology and vaccine design. Vaccines for many diseases remain elusive, and this project aims to improve our understanding of the precise regions within pathogens that are the targets for the killer T cells of the immune system. These regions, called epitopes, are likely to be key ingredients in many future vaccines. Although immunologists have gat ....Noncanonical epitope recognition by CD8+ T lymphocytes. This proposed research program will provide significant fundamental insight in the areas of immunology and vaccine design. Vaccines for many diseases remain elusive, and this project aims to improve our understanding of the precise regions within pathogens that are the targets for the killer T cells of the immune system. These regions, called epitopes, are likely to be key ingredients in many future vaccines. Although immunologists have gathered much information about such epitopes, recent studies have shown that some unexpected regions of pathogens are targets for killer T cells. This project will break new ground by utilising unbiased procedures to assess the relative contribution of these noncanonical epitopes to immunity.Read moreRead less
Biochemical, Genomic and Phenomic Analysis of Gastric Parietal Cells from Wildtype and Mutant Mice. The interface between the cell and its environment is the cell membrane. Signals, nutrients, and ions all have to cross this barrier. In addition, the cells contain many specialized intracellular membranous compartments. We know little about the signals that direct the synthesis of these structures and determine their final composition and shape. This grant will utilize acid secretory cells in the ....Biochemical, Genomic and Phenomic Analysis of Gastric Parietal Cells from Wildtype and Mutant Mice. The interface between the cell and its environment is the cell membrane. Signals, nutrients, and ions all have to cross this barrier. In addition, the cells contain many specialized intracellular membranous compartments. We know little about the signals that direct the synthesis of these structures and determine their final composition and shape. This grant will utilize acid secretory cells in the stomach to examine these questions because they contain a very extensive membrane system. We will use a state-of-the-art genetic and cell biological technologies to manipulate and analyse these cells in a whole animal setting.Read moreRead less