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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
Cytoprotection By Erythropoietin In Hypoxia-ischaemia Of The Kidney And Brain
Funder
National Health and Medical Research Council
Funding Amount
$477,661.00
Summary
We aim to make a significant research impact by describing the complex mechanisms responsible for protecting kidney and brain cells from stress caused by a lack of oxygen. In particular we will establish whether the compound erythropoietin (Epo), which occurs naturally in the human body but its human recombinant form can also be used as a treatment, may be useful in protecting cells from death following a shortage of oxygen. . We have already described how Epo can protect the kidney, but no one ....We aim to make a significant research impact by describing the complex mechanisms responsible for protecting kidney and brain cells from stress caused by a lack of oxygen. In particular we will establish whether the compound erythropoietin (Epo), which occurs naturally in the human body but its human recombinant form can also be used as a treatment, may be useful in protecting cells from death following a shortage of oxygen. . We have already described how Epo can protect the kidney, but no one has yet described its action on kidney cell differentiation or its effect on structural and vascular support in the injured kidney. When might Epo treatment be effective? Could it protect against chronic renal disease? Likewise, whilst more very pre-term babies survive, this is a crucial period when they are at heightened sensitivity to lack of oxygen and they are at risk of brain damage and poor development because of lack of maturation of key structural cells in the brain. The role of Epo in aiding brain cell maturation and on blood vessel formation and function in this faulty development period is not known. Both of these health problems are major issues causing huge costs to society both financial and emotional. Despite the early evidence of a useful role for Epo in human disease treatment, current experimental and clinical data demonstrate the importance of further thorough investigation of mechanisms and cellular pathways that will underpin improvements in clinical outcomes. A particular strength of our project is that by comparing similarities and differences in the kidney and brain, we will be able to elucidate the mechanisms of action of Epo and its analogues.Read moreRead less
Assembly Of Mitochondrial Respiratory Chain Complexes And Defects Associated With Disease
Funder
National Health and Medical Research Council
Funding Amount
$464,610.00
Summary
A group of protein assemblies termed respiratory complexes are found in the inner membrane of mitochondria in our cells and are responsible for producing most of our energy. These complexes consist of many different protein subunits and are built by the help of numerous known and unknown assembly factors. For example, assembly of Complex I of the respiratory chain requires 39 different proteins that are made outside mitochondria and are then transported inside to be somehow joined together with ....A group of protein assemblies termed respiratory complexes are found in the inner membrane of mitochondria in our cells and are responsible for producing most of our energy. These complexes consist of many different protein subunits and are built by the help of numerous known and unknown assembly factors. For example, assembly of Complex I of the respiratory chain requires 39 different proteins that are made outside mitochondria and are then transported inside to be somehow joined together with the 7 other subunits that are made by mitochondria. This is clearly a complicated procedure and we have little information on how its assembly is achieved. We do know however that mistakes in the assembly of these complexes (particularly Complex I) do happen. In Australia, about 50 children born each year have inherited disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others present later causing a range of degenerative diseases, particularly affecting brain, muscle and heart. Defects in the respiratory chain have also been implicated in Parkinson's disease, Alzheimer's disease, type-2 diabetes and in cell death. In order to understand how respiratory complex defects cause disease, we need to understand more about how these complexes are built. The aim of this proposal is to investigate how Complex I is assembled, how it interacts with other respiratory complexes, and to identify and characterise proteins that aid in its assembly. We will also analyse assembly defects in cells from patients with suspected respiratory complex deficiencies. This work will aid in our understanding of not only how protein complexes are built, but how defects in their assembly can cause disease. This will be informative to families of affected individuals and may aid in future diagnosis and prevention of diseases where defects in mitochondria are implicated.Read moreRead less
Target Of Rapamycin control of nutrient uptake. This project aims to study nutrient uptake in eukaryotes. It is expected to generate new knowledge of critical and conserved features of environmental and Target Of Rapamycin (TOR)-mediated control of nutrient uptake, specifically endocytosis, building on novel preliminary data that identifies novel TOR control points. The expected outcomes include new insights into mechanisms controlling nutrient uptake and fostering institutional collaboration. T ....Target Of Rapamycin control of nutrient uptake. This project aims to study nutrient uptake in eukaryotes. It is expected to generate new knowledge of critical and conserved features of environmental and Target Of Rapamycin (TOR)-mediated control of nutrient uptake, specifically endocytosis, building on novel preliminary data that identifies novel TOR control points. The expected outcomes include new insights into mechanisms controlling nutrient uptake and fostering institutional collaboration. This knowledge is highly relevant to any industry or research project utilising living organisms, as nutrient availability supports survival, cell growth and proliferation.Read moreRead less
How do cells survive nutrient stress? Insight into mechanisms. This project studies cell survival under nutrient stress in eukaryotes. Building on extensive preliminary data that identifies novel TOR (Target of Rapamycin) Complex 2 (TORC2) control points it expects to generate new knowledge of critical and conserved features of stress control of macroautophagy that ensures cell survival. It uses interdisciplinary and innovative approaches to validate and characterize nutrient-stress dependent si ....How do cells survive nutrient stress? Insight into mechanisms. This project studies cell survival under nutrient stress in eukaryotes. Building on extensive preliminary data that identifies novel TOR (Target of Rapamycin) Complex 2 (TORC2) control points it expects to generate new knowledge of critical and conserved features of stress control of macroautophagy that ensures cell survival. It uses interdisciplinary and innovative approaches to validate and characterize nutrient-stress dependent signaling. Expected outcomes include novel insights into environmental control of cell proliferation and forging cross institutional collaborations. This knowledge benefits basic and applied biology and is relevant to industries/projects utilizing living cells as nutrient supports cell survival and proliferation.Read moreRead less
Function and regulation of the Na+,K+-ATPase. The Na+,K+-ATPase is the major energy-consuming enzyme of animal cells. Its ion pumping is essential for numerous physiological functions (e.g. heart, kidney, brain). Molecular detail of its pumping mechanism is, however, lacking and its regulation is still unclear. We will use rapid reaction methods on purified enzyme in vitro to locate the rate-determining step of the enzyme cycle, determine its mechanism, investigate its regulation by sodium conce ....Function and regulation of the Na+,K+-ATPase. The Na+,K+-ATPase is the major energy-consuming enzyme of animal cells. Its ion pumping is essential for numerous physiological functions (e.g. heart, kidney, brain). Molecular detail of its pumping mechanism is, however, lacking and its regulation is still unclear. We will use rapid reaction methods on purified enzyme in vitro to locate the rate-determining step of the enzyme cycle, determine its mechanism, investigate its regulation by sodium concentration, phosphorylation and membrane composition, and isolate its charge-transporting steps. The results will have immediate impact on the understanding of the enzyme's mechanism, its metabolic control and its role in disease.Read moreRead less
Elucidation Of Trafficking Of The Menkes (MNK;ATP7A) Copper-transporting ATPase In Epthelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic free radicals. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and mad cow disease. Menkes disease is an inherited and usually lethal copper ....Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic free radicals. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and mad cow disease. Menkes disease is an inherited and usually lethal copper deficiency disorder in humans, and the diverse and detrimental symptoms of this disease related to organs and tissues described above is a stark indicator of the essentiality of copper. We have carried out extensive research on Menkes disease and in particular the Menkes protein which in normal individuals plays a major role in maintaining the copper balance in cells, i.e. enough copper to satisfy nutritional needs of cells but not too much which causes toxicity. The normal Menkes protein catalyses the transport of copper across membranes of cells to the areas where it is needed by copper-dependent enzymes and is essential for copper absorption into the body from the gut. The normal Menkes protein functions as a molecular pump. We have discovered that this protein can sense copper concentrations in the cell and when these reach potentially toxic levels it can move (traffic) via small vesicles to the plasma membrane which surrounds cells. There it pumps the excess copper out of the cell and returns to its original location. Our studies are directed to understanding the molecular mechanisms which permit this remarkable protein to achieve a copper balance in living cells. The findings will be of major significance in understanding and treating acquired and inherited diseases involving copper deficiency or copper toxicity including osteoporosis, cardiovascular disease, and Alzheimer's disease.Read moreRead less
The control of elongation factor 2 and its role in the regulation of protein synthesis. Protein synthesis is a key process in living cells. The main stage, elongation, is regulated through phosphorylation of elongation factor eEF2 in response to hormones, amino acids and cellular energy status, via changes in the activity of eEF2 kinase. We will study how these conditions control eEF2 kinase by studying its phosphorylation and identifying new kinases that regulate it. We will explore the role of ....The control of elongation factor 2 and its role in the regulation of protein synthesis. Protein synthesis is a key process in living cells. The main stage, elongation, is regulated through phosphorylation of elongation factor eEF2 in response to hormones, amino acids and cellular energy status, via changes in the activity of eEF2 kinase. We will study how these conditions control eEF2 kinase by studying its phosphorylation and identifying new kinases that regulate it. We will explore the role of eEF2 in controlling protein synthesis, seek new substrates for eEF2 kinase and initiate work to elucidate the structure of this unusual enzyme. This will enhance, in a range of ways, fundamental understanding of cell physiology.Read moreRead less
Gene Discovery and Functional Analysis of Copper Homeostasis Genes in Drosophila. Copper is a vital nutrient required for the formation and maintenance of bones, blood vessels and the central nervous system, but copper is also potentially toxic when in excess. Homeostatic mechanisms are needed to maintain safe levels of copper in the body and disruptions to these mechanisms are associated with disorders such as Alzheimer's disease, heart disease and osteoporosis. We are investigating the regulat ....Gene Discovery and Functional Analysis of Copper Homeostasis Genes in Drosophila. Copper is a vital nutrient required for the formation and maintenance of bones, blood vessels and the central nervous system, but copper is also potentially toxic when in excess. Homeostatic mechanisms are needed to maintain safe levels of copper in the body and disruptions to these mechanisms are associated with disorders such as Alzheimer's disease, heart disease and osteoporosis. We are investigating the regulation of a key copper pump, the Menkes protein, which helps control copper levels in the body and we are using the genetic advantages of the fruit fly Drosophila to discover new genes that regulate Menkes activity and therefore copper levels. These studies could lead to novel therapies for a range of copper-related disorders.Read moreRead less
THE MECHANISMS OF PHOTOPROTECTION IN PLANTS - A GENOMICS AND PHOTOPHYSICAL APPROACH. Coping with adverse environmental conditions is central to plant survival in nature so understanding the photoprotective mechanisms of light acclimation is important for crop improvement. Therefore, effective acclimatory mechanisms at whole plant, cellular and molecular levels are essential to accommodate short and long-term exposure to potentially photodamaging full sunlight and environmental stresses, such as ....THE MECHANISMS OF PHOTOPROTECTION IN PLANTS - A GENOMICS AND PHOTOPHYSICAL APPROACH. Coping with adverse environmental conditions is central to plant survival in nature so understanding the photoprotective mechanisms of light acclimation is important for crop improvement. Therefore, effective acclimatory mechanisms at whole plant, cellular and molecular levels are essential to accommodate short and long-term exposure to potentially photodamaging full sunlight and environmental stresses, such as drought and temperature extremes that lead to plant death or greatly reduced crop yields due to free radical damage. This project brings together a unique cross-disciplinary expertise in biophysics, biochemistry, physiology and genomics to elucidate the known mechanisms and identify unknown factors in photoprotection.Read moreRead less