Control Of Proteases In Infectious, Degenerative And Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$11,668,789.00
Summary
Proteases are enzymes that control key processes in humans. The research in this program will result in major discoveries in the field of proteases and their inhibitors, with a focus on inflammatory, cardiovascular and degenerative disease. The knowledge gained from this strong foundation of fundamental research will underpin the translational outcomes necessary to combat the debilitating effects of immunological dysfunction, conformational and cardiovascular disease.
Characterisation of the oxygen-sensing asparaginyl hydroxylase, FIH-1, and hydroxylase-specific antagonists. This research will provide fundamental information on how cells and whole organisms can sense and respond accordingly to oxygen deficiency. This information is fundamental for our understanding of embryo development and adult life in different environments, and central to the diagnosis and treatment of diseases such as stroke, cardiovascular disease, and cancer. This research will contrib ....Characterisation of the oxygen-sensing asparaginyl hydroxylase, FIH-1, and hydroxylase-specific antagonists. This research will provide fundamental information on how cells and whole organisms can sense and respond accordingly to oxygen deficiency. This information is fundamental for our understanding of embryo development and adult life in different environments, and central to the diagnosis and treatment of diseases such as stroke, cardiovascular disease, and cancer. This research will contribute to our basic knowledge of these processes, provide invaluable information about the specific genes and proteins involved, and provide direct information about the therapeutic potential of specific drugs or inhibitors designed to target this oxygen response in human disease.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
The Activation Of Lipoprotein Lipase By Apolipoprotein C-II
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a h ....Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a high blood-lipids that can lead to premature atherosclerosis. Regulation of lipoprotein lipase occurs via an interaction with the regulatory protein apolipoprotein C-II. Individuals with apolipoprotein C-II deficiency also exhibit abnormal plasma lipid levels with an associated increased risk of coronary heart disease. These considerations demonstrate that the activation of lipoprotein lipase by apolipoprotein C-II is pivotal to the maintenance of normal blood lipid levels. The present proposal will establish the structure and orientation of apolipoprotein C-II in a lipid environment and provide a structural model for the activation of lipoprotein lipase by apolipoprotein C-II. These molecular details will serve as a model for the regulatory interactions of other apolipoproteins within lipoprotein particles and will generate leads for the development of new strategies for the treatment of blood lipid irregularities.Read moreRead less
Novel mass spectrometry methods to assess cellular oxidative stress. This project will provide fundamental understanding to the biology of cell stress that may lead to novel approaches for treating age-related diseases. It has the potential to have a significant economic and social impact nationally and internationally and provide Australian scientists with new technologies to study challenging issues in biology.
Studies of the pi3-kinase enzyme family using selective inhibitors. The objective of this project is to study the function of the PI3-kinase enzyme family in blood platelets. To do this, inhibitors which block the action of specific family members, will be evaluated for their effects in assays of platelet function. The results will enhance our understanding of the way in which platelets and other cells respond to stimuli, and lead new approaches to designing novel drugs that block these response ....Studies of the pi3-kinase enzyme family using selective inhibitors. The objective of this project is to study the function of the PI3-kinase enzyme family in blood platelets. To do this, inhibitors which block the action of specific family members, will be evaluated for their effects in assays of platelet function. The results will enhance our understanding of the way in which platelets and other cells respond to stimuli, and lead new approaches to designing novel drugs that block these responses.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE190100668
Funder
Australian Research Council
Funding Amount
$422,574.00
Summary
Cysteamine dioxygenases: novel oxygen sensors implicated in hypoxia? This project aims to characterise and manipulate a novel oxygen sensing system, the cysteamine dioxygenases, to help understand how mammalian cells respond to low oxygen concentrations, a condition known as hypoxia. A number of the world’s most destructive diseases can impair oxygen delivery, altering biochemical landscapes. By understanding how cells respond to fluctuations in oxygen, the project expects to develop effective m ....Cysteamine dioxygenases: novel oxygen sensors implicated in hypoxia? This project aims to characterise and manipulate a novel oxygen sensing system, the cysteamine dioxygenases, to help understand how mammalian cells respond to low oxygen concentrations, a condition known as hypoxia. A number of the world’s most destructive diseases can impair oxygen delivery, altering biochemical landscapes. By understanding how cells respond to fluctuations in oxygen, the project expects to develop effective methods to treat these detrimental conditions. Characterisation of the cysteamine dioxygenases could establish a novel mechanism by which cells monitor changes in oxygen, assisting in understanding hypoxia and disease. The project will also enable new cysteine initiating substrates to be identified, allowing the full impact of this regulatory process to be appreciated in mammals.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
How cholesterol optimises ion pump function in animal membranes. This project aims to determine how cholesterol optimises ion pump function in animal membranes and to identify the major effects of cholesterol and its derivatives on membranes’ physical properties. All animal cells need high levels of cholesterol in the plasma membrane for survival. Insufficient cholesterol biosynthesis leads to severe birth defects. The need for cholesterol is likely linked to its acceleration of sodium pump acti ....How cholesterol optimises ion pump function in animal membranes. This project aims to determine how cholesterol optimises ion pump function in animal membranes and to identify the major effects of cholesterol and its derivatives on membranes’ physical properties. All animal cells need high levels of cholesterol in the plasma membrane for survival. Insufficient cholesterol biosynthesis leads to severe birth defects. The need for cholesterol is likely linked to its acceleration of sodium pump activity, essential to physiological processes including cell division, nerve, muscle and kidney activity. An expected benefit of the project is knowledge on the molecular origin of diseases associated with inhibition of cholesterol production, and a more complete understanding of the crucial role played by cholesterol via its effect on ion pumping towards the healthy functioning of vital organs, particularly in heart muscle and nerves.Read moreRead less
Lipid-protein interplay in the mechanism of the sodium pump. The sodium pump is the major energy-consuming enzyme of animal cells. Its ion pumping is essential to numerous physiological processes (e.g. nerve, muscle and kidney activity and the maintenance of cell volume). Because of its importance in so many cell functions, the enzyme must be able to respond to cellular conditions. Using measurements of the enzyme's activity in isolated membrane fragments and comparison with its behaviour in liv ....Lipid-protein interplay in the mechanism of the sodium pump. The sodium pump is the major energy-consuming enzyme of animal cells. Its ion pumping is essential to numerous physiological processes (e.g. nerve, muscle and kidney activity and the maintenance of cell volume). Because of its importance in so many cell functions, the enzyme must be able to respond to cellular conditions. Using measurements of the enzyme's activity in isolated membrane fragments and comparison with its behaviour in living cells, this project aims to determine how sodium pump activity is modulated by transmembrane electric potential and intramembrane electric field strength. Our project could provide fundamental new knowledge on how membrane protein function in general can be controlled by electrical properties of their lipid surroundings.Read moreRead less