Structural Characterisation Of A Natural Inhibitor Of Sporulation Bound To Its Histidine Kinase Target
Funder
National Health and Medical Research Council
Funding Amount
$261,000.00
Summary
Many bacteria, including some which are virulent pathogens such as anthrax (Bacillus anthracis), are able to enter a dormant state by forming spores (sporulation). These spores are extremely robust and may persist in the environment buried in the soil for example for hundreds of years. The initiation of sporulation occurs in response to changes in the cellular and environmental conditions which threaten the free replicating existence of the bacterium. The process of sporulation is controlled at ....Many bacteria, including some which are virulent pathogens such as anthrax (Bacillus anthracis), are able to enter a dormant state by forming spores (sporulation). These spores are extremely robust and may persist in the environment buried in the soil for example for hundreds of years. The initiation of sporulation occurs in response to changes in the cellular and environmental conditions which threaten the free replicating existence of the bacterium. The process of sporulation is controlled at the molecular level by a complex signaling relay. It is of course vital for the existence of the organism that control of sporulation is tightly regulated - preventing the onset of spore-formation in any but the desired circumstances. We aim to determine the three-dimensional structures of the molecules involved in this regulated process and how, by interacting with each other, they can pass on the signal to the bacterium to either start or stop the spore forming process. Ultimately, the results of this work might lead to antibacterial agents which could be used to control particularly dangerous strains of bacteria.Read moreRead less
Investigating the intercellular trafficking of proteins and RNA and its relevance to neurodegenerative diseases. Alzheimer's and prion diseases are neurodegenerative disorders associated with protein misfolding. This project brings together similar features of these diseases using novel cell- and animal-based studies to develop a greater understanding of the molecular basis of these disorders.
Discovery Early Career Researcher Award - Grant ID: DE120102263
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Export of effector proteins by P. falciparum to the infected red blood cell. Infection by the malaria parasite has lethal consequences for humans. The parasite exports hundreds of proteins via a translocon to commandeer the red blood cell. This project aims to determine the function of one of the major translocon components and determine if it is a viable target for anti-malarial drug development.
Structure And Interactions Of The Malarial Vaccine Candidate AMA1
Funder
National Health and Medical Research Council
Funding Amount
$351,000.00
Summary
Malaria remains one the most lethal infectious diseases in the world today. It is directly responsible for 1-2 million deaths annually, many of these in children under 5 years of age. More than 300 million clinical cases are reported annually and over 40% of the global population (in excess of 2 billion people) are at risk. There is an urgent need for a vaccine against this disease, particularly because of the recent increase in forms of the parasite resistant to many of the best anti-malarial d ....Malaria remains one the most lethal infectious diseases in the world today. It is directly responsible for 1-2 million deaths annually, many of these in children under 5 years of age. More than 300 million clinical cases are reported annually and over 40% of the global population (in excess of 2 billion people) are at risk. There is an urgent need for a vaccine against this disease, particularly because of the recent increase in forms of the parasite resistant to many of the best anti-malarial drugs. AMA1 is an asexual stage antigen and a leading vaccine candidate. Little is known about the function of this protein, but it has been proposed to play a role in invasion of red blood cells. A clearer understanding of the structure of parasite antigens such as AMA1 that induce a protective response in infected individuals would provide a stimulus to research into recombinant antigens as vaccines and a deeper understanding of host-parasite interactions. The aims of this project are to determine the three-dimensional structures of the three major structural domains of AMA1 and of the complete AMA1 antigen. We shall also determine the structures, both in aqueous solution and bound to AMA1, of small peptides identified by phage display as being capable of binding to AMA1 and blocking parasite entry into red blood cells. The overall goal of this work is to determine the structure of AMA1 and define the structural basis for its interaction with small peptides capable of blocking its activity as well as the structural features necessary for AMA1 to react with protective antibodies. The structure of AMA1 will provide a molecular basis for the design of engineered antigens capable of eliciting a protective immune response against AMA1. The inhibitory peptide structures will likewise provide a molecular basis for the design of non-peptidic blockers of AMA1. Either or both of these may be useful therapeutics leads in the fight against malaria.Read moreRead less
Characterization of erythroid differentiation related factor (EDRF): a novel a-globin binding protein. Hemoglobin, a four-subunit protein comprising two alpha and two beta polypeptide chains, is the essential oxygen transporter found in all mammals. Problems with the synthesis of hemoglobin can give rise to a range of common and serious human disorders, including thalassaemia and anemia. We have discovered a protein, EDRF, that appears to interact directly with alpha-globin (but not beta-globin) ....Characterization of erythroid differentiation related factor (EDRF): a novel a-globin binding protein. Hemoglobin, a four-subunit protein comprising two alpha and two beta polypeptide chains, is the essential oxygen transporter found in all mammals. Problems with the synthesis of hemoglobin can give rise to a range of common and serious human disorders, including thalassaemia and anemia. We have discovered a protein, EDRF, that appears to interact directly with alpha-globin (but not beta-globin) and to play a role in the regulation of hemoglobin production. We now seek to understand the nature of this interaction at a molecular level and mechanistic level.Read moreRead less
Molecular basis of the antifungal and antimalarial activity of a plant defensin. The plant defensin NaD1 has potent inhibitory activity against a number of agronomically important fungal pathogens. These species are major pathogens of cotton and other important agricultural crops such as canola and potatoes. These pathogens cause serious economic losses and threaten the future of the cotton industry in Australia. NaD1 also has potential as a new antibiotic for treatment of infections in human ....Molecular basis of the antifungal and antimalarial activity of a plant defensin. The plant defensin NaD1 has potent inhibitory activity against a number of agronomically important fungal pathogens. These species are major pathogens of cotton and other important agricultural crops such as canola and potatoes. These pathogens cause serious economic losses and threaten the future of the cotton industry in Australia. NaD1 also has potential as a new antibiotic for treatment of infections in humans.Read moreRead less
Determination of the mechanisms of immune system regulation of inflammation by the human protein, chaperonin 10. The aim of this project is to determine the mechanisms by which a human protein, chaperonin 10 (Cpn10), regulates the immune system and suppresses inflammation. When cells of the human immune system are challenged with lipopolysaccharide (LPS) (a product of bacterial infection), the pro-inflammatory cytokine TNF is released. Cpn10 has been shown to suppress production of TNF on chall ....Determination of the mechanisms of immune system regulation of inflammation by the human protein, chaperonin 10. The aim of this project is to determine the mechanisms by which a human protein, chaperonin 10 (Cpn10), regulates the immune system and suppresses inflammation. When cells of the human immune system are challenged with lipopolysaccharide (LPS) (a product of bacterial infection), the pro-inflammatory cytokine TNF is released. Cpn10 has been shown to suppress production of TNF on challenge of cells with LPS, while increasing the levels of the anti-inflammatory cytokine IL-10. Investigating the role of Cpn10 in modulating inflammation will contribute to the understanding and treatment of diseases associated with inflammation, including multiple sclerosis and rheumatoid arthritis.Read moreRead less
Ion transport in the malaria parasite and parasitised erythrocyte. This work will contribute to the national research effort in parasitology (an area in which the ARC has established a Research Network), as well as laying the groundwork for subsequent efforts (not part of this grant) to develop new antimalarial strategies. Although not yet endemic in Australia, malaria is a serious problem in the local region and, as the major developed nation in the region Australia has an obligation to make ....Ion transport in the malaria parasite and parasitised erythrocyte. This work will contribute to the national research effort in parasitology (an area in which the ARC has established a Research Network), as well as laying the groundwork for subsequent efforts (not part of this grant) to develop new antimalarial strategies. Although not yet endemic in Australia, malaria is a serious problem in the local region and, as the major developed nation in the region Australia has an obligation to make a significant contribution to research in this area. The work proposed here will contribute to Australia's meeting this obligation.Read moreRead less