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Defining the Regulatory Pool of Cholesterol in the Mammalian Cell. Heart disease remains the greatest killer of Australians and Alzheimer's disease represents a growing burden in our aging population. The information gained in this project will be invaluable in advancing our understanding of how cholesterol levels are controlled within the cell and will provide the groundwork for further research that can help to identify novel targets for new drugs to fight heart disease and Alzheimer's diseas ....Defining the Regulatory Pool of Cholesterol in the Mammalian Cell. Heart disease remains the greatest killer of Australians and Alzheimer's disease represents a growing burden in our aging population. The information gained in this project will be invaluable in advancing our understanding of how cholesterol levels are controlled within the cell and will provide the groundwork for further research that can help to identify novel targets for new drugs to fight heart disease and Alzheimer's disease.Read moreRead less
Cellular response to pro-oxidative myoglobin. The heart is vulnerable to oxidative damage as specialised muscle cells termed myocytes are unable to regenerate. Oxidative damage to myocytes decreases cell viability and in turn heart muscle function. Pro-oxidative forms of the protein myoglobin are present in the heart and may play a role in damaging myocytes. This study will determine whether a series of novel synthetic antioxidants inhibit myoglobin-mediated damage to heart muscle and preserve f ....Cellular response to pro-oxidative myoglobin. The heart is vulnerable to oxidative damage as specialised muscle cells termed myocytes are unable to regenerate. Oxidative damage to myocytes decreases cell viability and in turn heart muscle function. Pro-oxidative forms of the protein myoglobin are present in the heart and may play a role in damaging myocytes. This study will determine whether a series of novel synthetic antioxidants inhibit myoglobin-mediated damage to heart muscle and preserve function. This may lead to new therapies to combat cardiovascular disease and enable ageing Australians to maintain productive and independent lifestyles.Read moreRead less
Activation of Tissue Factor by a Disulphide-Bond Switch. This project will define the molecular mechanism of activation of tissue factor, the initiator of blood coagulation, and design and test novel antibody therapeutics that block this activation. The applicant suggests that tissue factor is activated by a disulphide-bond switch. Should this hypothesis prove correct it would be the first example of activation of a mammalian protein by this means and, moreover, would be very amenable to therape ....Activation of Tissue Factor by a Disulphide-Bond Switch. This project will define the molecular mechanism of activation of tissue factor, the initiator of blood coagulation, and design and test novel antibody therapeutics that block this activation. The applicant suggests that tissue factor is activated by a disulphide-bond switch. Should this hypothesis prove correct it would be the first example of activation of a mammalian protein by this means and, moreover, would be very amenable to therapeutic intervention because activation occurs on the membrane surface inside blood vessels. Tissue factor activation and thrombus formation is the precipitating event in acute myocardial infarction, unstable angina and ischemic stroke, which are responsible for the majority of deaths in Australia.Read moreRead less
Investigating the molecular function of alpha-Haemoglobin stabilising protein. The research described in this proposal will provide new insights into haemoglobin regulation and redox chemistry in erythrocytes. Deregulation of these processes gives rise to a number of debilitating diseases, including varieties of anaemia and thalassaemia-in Australia it is estimated that 3% of the population could be carriers of b-thalassaemia mutations. Given the contribution of free aHb to the pathology of b-th ....Investigating the molecular function of alpha-Haemoglobin stabilising protein. The research described in this proposal will provide new insights into haemoglobin regulation and redox chemistry in erythrocytes. Deregulation of these processes gives rise to a number of debilitating diseases, including varieties of anaemia and thalassaemia-in Australia it is estimated that 3% of the population could be carriers of b-thalassaemia mutations. Given the contribution of free aHb to the pathology of b-thalassaemia, understanding the specific aHb-binding factor, AHSP is a goal of national significance. In the long term, manipulation of AHSP function through gene therapy may have a direct role in the treatment of thalassaemia.Read moreRead less
YrdC translational control: physical and functional interactions, identification and influence of amino acid phosphorylation. This project will expand our basic understanding of the mechanisms with which a newly identified and highly conserved protein, YrdC203 regulates the process of protein synthesis from mRNA. This work will lead to basic insights into how gene expression is regulated at the level of translation, and generate valuable research tools, such as YrdC203 knockdown tools, peptide m ....YrdC translational control: physical and functional interactions, identification and influence of amino acid phosphorylation. This project will expand our basic understanding of the mechanisms with which a newly identified and highly conserved protein, YrdC203 regulates the process of protein synthesis from mRNA. This work will lead to basic insights into how gene expression is regulated at the level of translation, and generate valuable research tools, such as YrdC203 knockdown tools, peptide mimetics and decoys, phospho-specific and phospho-non specific antibodies. Exploitation of this breakthrough science will open up new avenues for therapeutic intervention in the future, while commercial exploitation of such reagents that recognise or interfere with YrdC203 will generate economic returns to Australia.Read moreRead less
Genome wide screening for gene products that regulate the celluar dynamics of lipid droplets. Obesity is a pandemic that if not stopped, will lead to huge social and economic problems in Australia. In essence, the hallmark of human obesity is the accumulation of cellular lipid droplets. This research will benefit Australia by providing a fundamental understanding of how lipid droplets are formed. This will have immediate international impact at the scientific level and will also provide novel ta ....Genome wide screening for gene products that regulate the celluar dynamics of lipid droplets. Obesity is a pandemic that if not stopped, will lead to huge social and economic problems in Australia. In essence, the hallmark of human obesity is the accumulation of cellular lipid droplets. This research will benefit Australia by providing a fundamental understanding of how lipid droplets are formed. This will have immediate international impact at the scientific level and will also provide novel targets and strategies for treating obesity. The proposed study will also benefit Australian agriculture by providing strategies to improve oil production from plant seeds. Read moreRead less
Molecular control of apoptosis and protein homeostasis. A million cells are produced every second by cell division. At the same time a million cells commit suicide by a process called apoptosis. When cells fail to die when they should they can develop into cancers. In heart attacks, stroke and neurodegenerative diseases, many cells appear to activate their self destruct mechanism to die unnecessarily. Drugs that can cause cancer cells to kill themselves, or drugs that prevent cells dying when th ....Molecular control of apoptosis and protein homeostasis. A million cells are produced every second by cell division. At the same time a million cells commit suicide by a process called apoptosis. When cells fail to die when they should they can develop into cancers. In heart attacks, stroke and neurodegenerative diseases, many cells appear to activate their self destruct mechanism to die unnecessarily. Drugs that can cause cancer cells to kill themselves, or drugs that prevent cells dying when they shouldn't, would make a major impact on many important diseases. Understanding the molecular mechanisms of cell death is the first step towards developing these drugs.Read moreRead less
Examination of the Calcium Signalling Dynamics Linked to Integrin Adhesion Utilising a Novel Micro-imaging System. This study aims at increasing our understanding of the fundamental cell processes that allow cells to adhere to surfaces. The proposed study will lead to a greater understanding of the calcium signalling mechanisms that are fundamental to diverse biological phenomena such as, tissue regeneration and repair, blood clotting, cancer metastasis, and neuronal cell function. From a preven ....Examination of the Calcium Signalling Dynamics Linked to Integrin Adhesion Utilising a Novel Micro-imaging System. This study aims at increasing our understanding of the fundamental cell processes that allow cells to adhere to surfaces. The proposed study will lead to a greater understanding of the calcium signalling mechanisms that are fundamental to diverse biological phenomena such as, tissue regeneration and repair, blood clotting, cancer metastasis, and neuronal cell function. From a preventative health perspective, the investigation of platelet calcium signalling will greatly accelerate the development of new pharmaceuticals to tackle acute and chronic cardiovascular diseases, such as stroke, heart attack and artherosclerosis. Read moreRead less
Biochemical properties of S-nitroso-myoglobin and its role in regulating nitric oxide bio-availability. Nitric oxide (NO) stimulates blood vessel dilation. Vessel dilation is essential to maintaining blood pressure. Altered NO-regulation leads to vessel dysfunction. Within blood vessels, myoglobin regulates NO concentrations through oxidation and binding reactions. In contrast, S-nitroso-myoglobin represents a novel source of NO in humans. The goal of this study is to expand the knowledge on ....Biochemical properties of S-nitroso-myoglobin and its role in regulating nitric oxide bio-availability. Nitric oxide (NO) stimulates blood vessel dilation. Vessel dilation is essential to maintaining blood pressure. Altered NO-regulation leads to vessel dysfunction. Within blood vessels, myoglobin regulates NO concentrations through oxidation and binding reactions. In contrast, S-nitroso-myoglobin represents a novel source of NO in humans. The goal of this study is to expand the knowledge on NO-regulation by myoglobin through determining S-nitroso-myoglobin's - chemical stability, rates of formation and decay, concentration in human vessels and whether it can cause blood vessel dilation similar to authentic NO. Such novel data represents a major fundamental advance in understanding the role of myoglobin in NO-homeostasis.Read moreRead less
Investigating the structure, function and inhibition of the adrenaline-synthesizing enzyme PNMT. We determined the structure of the enzyme PNMT and we plan to use this in the design of PNMT inhibitors to enable us to probe the role of adrenaline and PNMT in the central nervous system. As part of this work, we will further characterise the structure of PNMT by crystallography and mutagenesis. The significance is that designed PNMT inhibitors could eventually be used as leads in the development of ....Investigating the structure, function and inhibition of the adrenaline-synthesizing enzyme PNMT. We determined the structure of the enzyme PNMT and we plan to use this in the design of PNMT inhibitors to enable us to probe the role of adrenaline and PNMT in the central nervous system. As part of this work, we will further characterise the structure of PNMT by crystallography and mutagenesis. The significance is that designed PNMT inhibitors could eventually be used as leads in the development of compounds with novel pharmacological and therapeutic activity. Furthermore, our analysis of PNMT will determine rules that can be applied to the design of new methyltransferase enzymes with novel functions.Read moreRead less