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
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
Gain from pain: new tools from venomous animals for exploring pain pathways. This project aims to explore animal venoms for new pain-causing toxins, to determine their structure and mechanism of action. Many venomous animals use their venom defensively and envenomation is frequently associated with rapid and often excruciating pain. In most cases the molecular mechanisms by which they achieve this is unknown. Using biochemical, pharmacological and biophysical techniques, this project expects to ....Gain from pain: new tools from venomous animals for exploring pain pathways. This project aims to explore animal venoms for new pain-causing toxins, to determine their structure and mechanism of action. Many venomous animals use their venom defensively and envenomation is frequently associated with rapid and often excruciating pain. In most cases the molecular mechanisms by which they achieve this is unknown. Using biochemical, pharmacological and biophysical techniques, this project expects to uncover toxins that employ new mechanisms of pain signalling, leading to new insights into pain physiology.Read moreRead less
Identification of novel biomarkers in tears for prostate cancer diagnosis and prognosis. The purpose of this study is to identify novel biomarkers in the tears of patients with CaP. The use of the several techniques will increase the chance of success and enable us to find more diagnostic markers. If successful, the identified proteins may be used to diagnose and determine the stage of cancer. This will help guide clinicians in choosing the best treatment methods for an individual patient. The m ....Identification of novel biomarkers in tears for prostate cancer diagnosis and prognosis. The purpose of this study is to identify novel biomarkers in the tears of patients with CaP. The use of the several techniques will increase the chance of success and enable us to find more diagnostic markers. If successful, the identified proteins may be used to diagnose and determine the stage of cancer. This will help guide clinicians in choosing the best treatment methods for an individual patient. The markers may also be used to monitor the disease progress and the effects of treatment. The results from this study may improve the prognosis of CaP patients.Read moreRead less
Identification of novel biomarkers for diabetic retinopathy in tears. There are around 134,000 people with diabetic retinopathy in Australia. The disease affects patients' physical and mental state and economical and social cost is enormous. This research aims to find new biomarkers for the disease which may lead to better treatment and management. Patient's quality of life may be significantly improved by early diagnosis and treatment and the burden to the community reduced. This project also g ....Identification of novel biomarkers for diabetic retinopathy in tears. There are around 134,000 people with diabetic retinopathy in Australia. The disease affects patients' physical and mental state and economical and social cost is enormous. This research aims to find new biomarkers for the disease which may lead to better treatment and management. Patient's quality of life may be significantly improved by early diagnosis and treatment and the burden to the community reduced. This project also gives industrial partners the opportunity to develop new products to diagnose and monitor the disease.Read moreRead less
Special Research Initiatives - Grant ID: SR0354892
Funder
Australian Research Council
Funding Amount
$40,000.00
Summary
The Australian Protease Network. Proteases are pivotal enzymes during birth, life, ageing and death of all organisms. Proteases regulate most physiological processes by controlling protein activation, synthesis and turnover and are essential for replication and spread of viruses, bacteria and parasites that cause infectious diseases. Blockbuster drugs and diagnostics already target a few proteases. Australians have made innovative contributions individually to understanding and regulating these ....The Australian Protease Network. Proteases are pivotal enzymes during birth, life, ageing and death of all organisms. Proteases regulate most physiological processes by controlling protein activation, synthesis and turnover and are essential for replication and spread of viruses, bacteria and parasites that cause infectious diseases. Blockbuster drugs and diagnostics already target a few proteases. Australians have made innovative contributions individually to understanding and regulating these enzymes. However this initiative aims to network their efforts by value-adding to the current protease research through promoting national and international collaborations to improve our understanding of biology, and encourage exploitation of proteases/inhibitors/receptors for pharmaceutical and industrial applications.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0882913
Funder
Australian Research Council
Funding Amount
$300,000.00
Summary
Mass spectrometry facility for the quantitation and analysis of post-translationally modified peptides. This proposal will address a gap in our mass spectrometry capabilities and aid in our understanding of the cellular immune response and investigate the chemical diversity of the targets of immunity. This proposal has broad implications in the basic immunology of antigen presentation, in biomarker discovery as well as in the design of new vaccines in infectious disease and cancer and the develo ....Mass spectrometry facility for the quantitation and analysis of post-translationally modified peptides. This proposal will address a gap in our mass spectrometry capabilities and aid in our understanding of the cellular immune response and investigate the chemical diversity of the targets of immunity. This proposal has broad implications in the basic immunology of antigen presentation, in biomarker discovery as well as in the design of new vaccines in infectious disease and cancer and the development of therapies for autoimmune diseases. In addition to these key scientific outcomes this project will also facilitate the training of several new personnel in a skill area for which there is a critical shortage (mass spectrometry) and promote cross-disciplinary skills (immunology, biochemistry, proteomics).Read moreRead less
Ultrasensitive electrochemical biosensors. This project aims to develop novel proteins that can convert biochemical cues into electronic signals. Using protein engineering, this project will produce redox protein-based OFF switches. The project expects that the use of the OFF-switches (as opposed to ON switches) will simplify biosensor design and create a new class of sensory architectures. Integration of OFF-switch-based biosensors with an enzymatic signal amplification circuit is expected to y ....Ultrasensitive electrochemical biosensors. This project aims to develop novel proteins that can convert biochemical cues into electronic signals. Using protein engineering, this project will produce redox protein-based OFF switches. The project expects that the use of the OFF-switches (as opposed to ON switches) will simplify biosensor design and create a new class of sensory architectures. Integration of OFF-switch-based biosensors with an enzymatic signal amplification circuit is expected to yield ultrasensitive sensory systems with near-real-time response. The project will address a need for new technologies that enable collection of physiological and environmental information rapidly, and at low cost outside of the specialised laboratories.Read moreRead less