Mechanistic studies on the oxidation of amino acids, peptides and proteins and its biological consequences. Exposure of amino acids and proteins to radicals, oxidants, UV light, and metal ions results in oxidation, with consequent alteration to protein structure and function. It has been shown that these reactions occur during food spoilage, exposure of plants to excess UV light, and in a number of human diseases (e.g. heart disease and cancer). Despite evidence for a key role for protein oxidat ....Mechanistic studies on the oxidation of amino acids, peptides and proteins and its biological consequences. Exposure of amino acids and proteins to radicals, oxidants, UV light, and metal ions results in oxidation, with consequent alteration to protein structure and function. It has been shown that these reactions occur during food spoilage, exposure of plants to excess UV light, and in a number of human diseases (e.g. heart disease and cancer). Despite evidence for a key role for protein oxidation in these events, the fundamental chemistry and biochemistry of protein oxidation is incompletely understood. This is addressed in this project. Knowledge of the mechanisms of these reactions is a vital pre-requisite to the rational design of preventative strategies that might enhance food quality, minimise UV damage and enhance human health.Read moreRead less
Functional Dissection of the Bacterial Replisome. We now have the complete sequences of genes in humans and many other organisms, but we know much less about how the protein products of the genes communicate with each other to create and grow cells. Australia has recently invested heavily in state-of-the-art instruments that can be used to tackle these problems. This project will involve close interaction of four laboratories to use new instruments to determine how a large assembly of proteins i ....Functional Dissection of the Bacterial Replisome. We now have the complete sequences of genes in humans and many other organisms, but we know much less about how the protein products of the genes communicate with each other to create and grow cells. Australia has recently invested heavily in state-of-the-art instruments that can be used to tackle these problems. This project will involve close interaction of four laboratories to use new instruments to determine how a large assembly of proteins interact in a biological machine that makes DNA. This process occurs in similar ways in all organisms, and is essential for life. Understanding how DNA is made will help scientists to develop new antibacterial drugs, and learn how to make practical use of molecular machines that imitate biology.Read moreRead less
Mapping Protein Contacts and Conformational Changes in Macromolecular Assemblies. We now have a great deal of information about the structures of proteins that interact to do much of the chemistry that governs the lives of cells and organisms, but are just beginning to understand how proteins communicate with each other in the large, dynamic molecular machines that carry out many cellular functions. Australia has invested in expensive instrumentation that can be used in conjunction with new labo ....Mapping Protein Contacts and Conformational Changes in Macromolecular Assemblies. We now have a great deal of information about the structures of proteins that interact to do much of the chemistry that governs the lives of cells and organisms, but are just beginning to understand how proteins communicate with each other in the large, dynamic molecular machines that carry out many cellular functions. Australia has invested in expensive instrumentation that can be used in conjunction with new laboratory methods to develop better understanding of how these machines work, and how they malfunction in disease. This project will bring together four scientists with a unique combination of expertise and novel technologies to develop understanding of changes in structure of a large protein complex in different functional states.Read moreRead less
Molecular Interactions in the Eubacterial Replisome: A Paradigm for Study of Dynamic Macromolecular Machines. Many pathogenic bacteria have developed resistance to antibiotics in common use, and new drugs are urgently required to kill them. Copying of their chromosomes before they divide into two new cells is essential for bacteria to live, so DNA synthesis is a good process to target for development of new antibiotics. This project will use state-of-the-art equipment available in several labora ....Molecular Interactions in the Eubacterial Replisome: A Paradigm for Study of Dynamic Macromolecular Machines. Many pathogenic bacteria have developed resistance to antibiotics in common use, and new drugs are urgently required to kill them. Copying of their chromosomes before they divide into two new cells is essential for bacteria to live, so DNA synthesis is a good process to target for development of new antibiotics. This project will use state-of-the-art equipment available in several laboratories in Australia and overseas to develop new understanding of how the molecular machine that copies DNA works. This k nowledge could lead to new drugs, and will give us new information about how cellular machines function.Read moreRead less
Fragment Based Screening for new Antibiotics by Protein X-Ray Crystallography. Due in part to rising levels of antibiotic resistance, the death toll from pathogenic bacteria is expected to skyrocket over the next 15 years. There is therefore a pressing need for new antibiotics to treat bacterial infection. This project will use a relatively new discovery tool called fragment based screening to discover a new generation of antibacterial agents. This tool will allow for the rapid economical discov ....Fragment Based Screening for new Antibiotics by Protein X-Ray Crystallography. Due in part to rising levels of antibiotic resistance, the death toll from pathogenic bacteria is expected to skyrocket over the next 15 years. There is therefore a pressing need for new antibiotics to treat bacterial infection. This project will use a relatively new discovery tool called fragment based screening to discover a new generation of antibacterial agents. This tool will allow for the rapid economical discovery of new drugs, and will complement other investments in Australian biotechnology infrastructure.Read moreRead less
Streamlining the dynamin epilepsy drug pipeline. Epilepsy affects up to one percent of Australia's population, yet one in three fail to respond to current medications. Our results will greatly impact on development of future epilepsy therapy. Identification of a new target for epileptic will allow better drug design to improve the potency of our lead drugs. This holds hope that new generation drugs will be more effective. The drugs are predicted to have fewer complications and side-effects. Th ....Streamlining the dynamin epilepsy drug pipeline. Epilepsy affects up to one percent of Australia's population, yet one in three fail to respond to current medications. Our results will greatly impact on development of future epilepsy therapy. Identification of a new target for epileptic will allow better drug design to improve the potency of our lead drugs. This holds hope that new generation drugs will be more effective. The drugs are predicted to have fewer complications and side-effects. The outcome has the potential to vastly improve prospects for up to 200,000 Australians. Intellectual property (IP) retained in Australia will generate future biotechnology industry. The novel chemical biological approaches will facilitate training of future generations of Australian scientists.Read moreRead less
Mechanisms and consequences of oxidation of glycosaminoglycans, proteins and proteoglycans by myeloperoxidase-derived oxidants. Atherosclerosis (hardening of the arteries) is responsible for the death of 40% of the population of developed, and developing, countries including Australia. Rupture of the fibrous cap of atherosclerotic lesions is responsible for most sudden deaths from heart disease and stokes, but is a poorly understood process. Evidence has been presented for a role for oxidation r ....Mechanisms and consequences of oxidation of glycosaminoglycans, proteins and proteoglycans by myeloperoxidase-derived oxidants. Atherosclerosis (hardening of the arteries) is responsible for the death of 40% of the population of developed, and developing, countries including Australia. Rupture of the fibrous cap of atherosclerotic lesions is responsible for most sudden deaths from heart disease and stokes, but is a poorly understood process. Evidence has been presented for a role for oxidation reactions in weakening the structure of lesions and making them prone to rupture. Little is known about the fundamental chemistry of such damage; this will be addressed in the proposed program. The data obtained will underpin the development of new preventative and protective strategies to minimise lesion rupture and deaths from this major disease.Read moreRead less
Mechanisms and consequences of myeloperoxidase-mediated damage to glycosaminoglycans, proteins and proteoglycans. Atherosclerosis (hardening of the arteries) is responsible for the death of 40% of the population of developed, and developing, countries including Australia. Rupture of the fibrous cap of atherosclerotic lesions is responsible for most sudden deaths from heart disease and stokes, but is a poorly understood process. Evidence has been presented for a role for oxidation reactions in we ....Mechanisms and consequences of myeloperoxidase-mediated damage to glycosaminoglycans, proteins and proteoglycans. Atherosclerosis (hardening of the arteries) is responsible for the death of 40% of the population of developed, and developing, countries including Australia. Rupture of the fibrous cap of atherosclerotic lesions is responsible for most sudden deaths from heart disease and stokes, but is a poorly understood process. Evidence has been presented for a role for oxidation reactions in weakening the structure of lesions and making them prone to rupture. Little is known about the fundamental chemistry of such damage; this will be addressed in the proposed program. The data obtained will underpin the development of new preventative and protective strategies to minimise lesion rupture and deaths from this major disease.Read moreRead less
Proteomics of the Influenza Virus for In-field Surveillance. The influenza virus continues to pose a serious health risk to Australians and remains a leading cause of death. The molecular characterisation of emerging strains of the virus lies at the heart of current surveillance procedures vital to vaccine preparation and the development of new anti-viral drugs. This research will advance a world-first proteomics surveillance of the virus developed in this laboratory that will enable it to be ch ....Proteomics of the Influenza Virus for In-field Surveillance. The influenza virus continues to pose a serious health risk to Australians and remains a leading cause of death. The molecular characterisation of emerging strains of the virus lies at the heart of current surveillance procedures vital to vaccine preparation and the development of new anti-viral drugs. This research will advance a world-first proteomics surveillance of the virus developed in this laboratory that will enable it to be characterised in-field at the site(s) of infection outbreaks. This rapid response is vital, particularly in the event of a pandemic or a deliberate release of the virus in a bioterrorist attack.Read moreRead less
The Chemistry and Biochemistry of Chromium: Cancer and Nutrition. Of all of the human carcinogens, chromium(VI) has the highest level of occupational exposure, and is of increasing concern as an environmental carcinogen, as highlighted by the film Erin Brockovitch. Similarly, chromium(III) nutritional supplement consumption by humans and animals is rising rapidly, despite mounting concerns about their cancer risks. However, the complexity of Cr biochemistry is such that it is still poorly unde ....The Chemistry and Biochemistry of Chromium: Cancer and Nutrition. Of all of the human carcinogens, chromium(VI) has the highest level of occupational exposure, and is of increasing concern as an environmental carcinogen, as highlighted by the film Erin Brockovitch. Similarly, chromium(III) nutritional supplement consumption by humans and animals is rising rapidly, despite mounting concerns about their cancer risks. However, the complexity of Cr biochemistry is such that it is still poorly understood. This project aims at providing new insights into Cr biochemistry that are of relevance in evaluating risk factors for occupational and environmental exposure and for producing safer Cr dietary supplements.Read moreRead less