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The regulation of signalling molecules in Saccharomyces Cerevisiae by inositol polyphosphate 5-phosphatases. Phosphoinositide signalling molecules regulate the actin cytoskeleton, secretion, vesicular trafficking and cell growth and death. We have identified, cloned and characterised a family of signal terminating enzymes called inositol polyphosphate 5-phosphatases (5-phosphatases) that regulate phosphoinositide signalling molecules. We have cloned and characterised four distinct 5-phosphatases ....The regulation of signalling molecules in Saccharomyces Cerevisiae by inositol polyphosphate 5-phosphatases. Phosphoinositide signalling molecules regulate the actin cytoskeleton, secretion, vesicular trafficking and cell growth and death. We have identified, cloned and characterised a family of signal terminating enzymes called inositol polyphosphate 5-phosphatases (5-phosphatases) that regulate phosphoinositide signalling molecules. We have cloned and characterised four distinct 5-phosphatases in the yeast Saccharomyces Cerevisiae and demonstrated by both deletion and overexpression studies that these enzymes regulate the actin cytoskeleton, endocytosis and secretion. This research proposal aims to investigate the signalling complexes the 5-phosphatases form with specific actin binding and or regulatory proteins, investigate the complex interactions of phosphoinositide lipid phosphatases and the roles they play in regulating secretion from the endoplasmic reticulum and finally characterize a novel 5-phosphatase that we have recently identified. Collectively the outcome of these studies will provide novel information about the functionallly significant signalling pathways regulated by this important enzyme family.Read moreRead less
Probing JNK MAPK function with peptide inhibitors. It has generally been accepted that the JNK MAPK family of protein kinases is rapidly and potently activated following the exposure of mammalian cells to stresses and cytokines. However, their biological role has remained controversial. We believe that this problem reflects the lack of a generally applicable and specific JNK MAPK inhibitor. In this project we continue our characterisation of a small peptide inhibitor developed in our laboratori ....Probing JNK MAPK function with peptide inhibitors. It has generally been accepted that the JNK MAPK family of protein kinases is rapidly and potently activated following the exposure of mammalian cells to stresses and cytokines. However, their biological role has remained controversial. We believe that this problem reflects the lack of a generally applicable and specific JNK MAPK inhibitor. In this project we continue our characterisation of a small peptide inhibitor developed in our laboratories. We aim to determine its mechanism of inhibition, the specificity of interaction, and to evolve more effective inhibitors. With these new inhibitors, we can effectively address the biological roles of these kinases.Read moreRead less
New inhibitors of HIV based on cellular enzymes. Over 39 million people are infected with HIV worldwide. However, none of the most highly affected countries have yet reached the peak in AIDS-related illness and death, thus the global impact of HIV/AIDS will get significantly worse, before it gets better.
In Australia, HIV is again on the rise. Ironically, improved treatments that have extended life expectancy will cause the number of HIV infected Australians to rise for many years to come. ....New inhibitors of HIV based on cellular enzymes. Over 39 million people are infected with HIV worldwide. However, none of the most highly affected countries have yet reached the peak in AIDS-related illness and death, thus the global impact of HIV/AIDS will get significantly worse, before it gets better.
In Australia, HIV is again on the rise. Ironically, improved treatments that have extended life expectancy will cause the number of HIV infected Australians to rise for many years to come. Therefore many Australians will suffer from the combined impact of the AIDS illness itself, opportunistic infections, the side-effects of treatment and natural aging. We aim to develop new drugs to combat this disease to help people everywhere lead happier, healthier and more productive lives.Read moreRead less
Isolation and analysis of novel caspases. Apoptosis is an evolutionarily conserved cellular process which must be tightly controlled for normal development and to avoid disease. Rapid progress has been made recently in the elucidation of apoptotic pathways, but many important components are likely still unknown. The caspases constitute the effector arm of apoptotic signalling pathways and some members play important roles in cytokine maturation. We aim to identify novel caspases using an innovat ....Isolation and analysis of novel caspases. Apoptosis is an evolutionarily conserved cellular process which must be tightly controlled for normal development and to avoid disease. Rapid progress has been made recently in the elucidation of apoptotic pathways, but many important components are likely still unknown. The caspases constitute the effector arm of apoptotic signalling pathways and some members play important roles in cytokine maturation. We aim to identify novel caspases using an innovative technique, and to characterise their function and regulation. Molecules identified in this project may be candidate targets for therapies which modulate apoptosis for treatment or prevention of disease, or diagnostic reagent development.Read moreRead less
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
Regulation and function of a novel protein tyrosine phosphatase. A cell's ability to respond to its extracellular environment involves a complex and highly organised series of events referred to as cellular signalling. These signalling processes regulate fundamental cellular processes that underlie the growth and development of all living organisms. This proposal focuses on a group of enzymes known as the protein tyrosine phosphatases and their ability to regulate tyrosine phosphorylation-depe ....Regulation and function of a novel protein tyrosine phosphatase. A cell's ability to respond to its extracellular environment involves a complex and highly organised series of events referred to as cellular signalling. These signalling processes regulate fundamental cellular processes that underlie the growth and development of all living organisms. This proposal focuses on a group of enzymes known as the protein tyrosine phosphatases and their ability to regulate tyrosine phosphorylation-dependent signalling. We have identified a novel human protein tyrosine phosphatase and we aim to characterise its regulation and biological function.Read moreRead less
Coordinating energy metabolism to enhance exercise capacity. Diet and exercise contribute to health and ageing productively whereas high caloric diets and sedentary life styles are deleterious. The enzyme AMPK regulates energy metabolism in response to diet and exercise and by studying it we expect to learn why diet and exercise are beneficial at the molecular level. This may allow the development of nutritional, exercise and drug strategies to enhance exercise capacity and well being during ....Coordinating energy metabolism to enhance exercise capacity. Diet and exercise contribute to health and ageing productively whereas high caloric diets and sedentary life styles are deleterious. The enzyme AMPK regulates energy metabolism in response to diet and exercise and by studying it we expect to learn why diet and exercise are beneficial at the molecular level. This may allow the development of nutritional, exercise and drug strategies to enhance exercise capacity and well being during ageing as well as suppress age onset diseases that include obesity diabetes cardiovascular disease hypertension and neurodegeneration.Read moreRead less
Systems therapeutics for metabolism: AMPK isoform specific drugs. Living cells have to maintain a steady balance between energy production and consumption in order to function properly. A key regulator of energy balance is an enzyme known as 5' AMP-activated protein kinase (AMPK), which regulates the burning and storage of fuels such as fat and sugars, in response to changes in energy demand. This project will provide a major advancement in our understanding of the regulation of AMPK at the mo ....Systems therapeutics for metabolism: AMPK isoform specific drugs. Living cells have to maintain a steady balance between energy production and consumption in order to function properly. A key regulator of energy balance is an enzyme known as 5' AMP-activated protein kinase (AMPK), which regulates the burning and storage of fuels such as fat and sugars, in response to changes in energy demand. This project will provide a major advancement in our understanding of the regulation of AMPK at the molecular level, and lay the foundations for the development of more effective drugs to treat energy balance disorders such as obesity and Type 2 diabetes. Furthermore, this proposal will contribute to enriching Australia's international profile and competitiveness in this important area of research.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
Characterisation of a novel protein tyrosine phosphatase. A cells ability to respond to its extracellular environment involves a complex and highly organised series of events referred to as cellular signalling. These signalling processes regulate fundamental cellular events that underlie the growth and development of all living organisms. This proposal focuses on a group of enzymes known as the protein tyrosine phosphatases and their ability to regulate tyrosine phosphorylation-dependent signa ....Characterisation of a novel protein tyrosine phosphatase. A cells ability to respond to its extracellular environment involves a complex and highly organised series of events referred to as cellular signalling. These signalling processes regulate fundamental cellular events that underlie the growth and development of all living organisms. This proposal focuses on a group of enzymes known as the protein tyrosine phosphatases and their ability to regulate tyrosine phosphorylation-dependent signalling. We have identified a novel human protein tyrosine phosphatase and we aim to characterise its function and the mechanism by which it is regulated.Read moreRead less