Regulation Of PtdIns(3,4,5)P3 By Inositol Polyphosphate 5-phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5- ....Growing cells respond to growth factors by dividing and proliferating. Uncontrolled cell growth leads to cancer. Signals are released from the cell membrane following growth factor stimulation, that communicate via a complex network of intracellular signalling molecules, that instruct the nucleus to divide. One critical signalling network that mediates cell growth are the phosphoinositide messenger molecules. These signals are switched off by a family of proteins called inositol polyphosphate 5-phosphatases. We propose the 5-phosphatases are essential for normal cell growth. Several studies have suggested in their absence tumour formation may occurr. We have identified a new member of this enzyme family called SHIP-2. This proposal aims to investigate the mechanisms by which this enzyme family metabolises signalling molecules and thereby regulates cell growth. We will also characterize how the 5-phosphatases control the normal pathways by which primitive cells differeniate into mature cells.Read moreRead less
Post-genomic investigation of the relict plastid and mitochondrion of malaria parasites. Malaria is a major global health problem. The malaria parasite has two substructures, a relict chloroplast and a mitochondrion, that are excellent targets for new and existing drugs. However, we do not know the key functions of these two compartments. The entire genetic blueprint (genome) is now available for the malaria parasite and I propose to determine exactly which parts of the genome service the rel ....Post-genomic investigation of the relict plastid and mitochondrion of malaria parasites. Malaria is a major global health problem. The malaria parasite has two substructures, a relict chloroplast and a mitochondrion, that are excellent targets for new and existing drugs. However, we do not know the key functions of these two compartments. The entire genetic blueprint (genome) is now available for the malaria parasite and I propose to determine exactly which parts of the genome service the relict chloroplast and mitochondria. This will sketch out a picture of their inner workings. Armed with this information we can take a rational approach to seeking an Achilles? Heel of malaria against which parasite-specific drugs can be developed.Read moreRead less
Inhibition of pro-inflammatory cytokine secretion- A new route to therapeutics of chronic inflammatory disease. Chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease, affect millions of people leading to considerable suffering, economic loss and premature death. Anti-TNF treatments have recently shown success in the treatment of rheumatoid arthritis, inflammatory bowel disease and other conditions, however, a substantial number of patients (~50%) do not re ....Inhibition of pro-inflammatory cytokine secretion- A new route to therapeutics of chronic inflammatory disease. Chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease, affect millions of people leading to considerable suffering, economic loss and premature death. Anti-TNF treatments have recently shown success in the treatment of rheumatoid arthritis, inflammatory bowel disease and other conditions, however, a substantial number of patients (~50%) do not respond to the current TNF treatments. Improved anti-TNF strategies would provide enhanced health outcomes and welcome relief to many Australians. In addition, the economic benefit of the TNF market is very substantial. Therefore the potential impact of this research is very high both for health care and economical potential.Read moreRead less
Shaping a signal: studies on non-contiguous residues in an intracellular serpin that constitute a novel nuclear protein import signal. Eukaryotic cells contain membrane-bound organelles like the nucleus, endoplasmic reticulum and mitochondria, and use specific mechanisms to direct proteins from their site of synthesis to their target organelle. In nuclear proteins, sequence motifs termed nuclear localization signals (NLSs) direct engagement with the nuclear pore complex and translocation from cy ....Shaping a signal: studies on non-contiguous residues in an intracellular serpin that constitute a novel nuclear protein import signal. Eukaryotic cells contain membrane-bound organelles like the nucleus, endoplasmic reticulum and mitochondria, and use specific mechanisms to direct proteins from their site of synthesis to their target organelle. In nuclear proteins, sequence motifs termed nuclear localization signals (NLSs) direct engagement with the nuclear pore complex and translocation from cytoplasm to nucleus. All NLSs described so far consist of 5-7 contiguous basic residues. We propose to study a novel NLS that we recently discovered on an intracellular serpin. This comprises non-contiguous residues that together form a basic "patch" on the mature protein, and is the first example of a conformational NLS.Read moreRead less
The Molecular Basis of Copper Metabolism in Sheep. The unusual copper metabolism of sheep represents a significant agricultural problem. They are very susceptible to copper deficiency, but readily accumulate copper to toxic levels in the liver leading to fatal liver failure. We propose to elucidate the reason for the copper accumulation phenotype of sheep. We are focussing on WND, a copper transporter responsible for copper excretion into bile. We discovered a novel form of sheep WND designated ....The Molecular Basis of Copper Metabolism in Sheep. The unusual copper metabolism of sheep represents a significant agricultural problem. They are very susceptible to copper deficiency, but readily accumulate copper to toxic levels in the liver leading to fatal liver failure. We propose to elucidate the reason for the copper accumulation phenotype of sheep. We are focussing on WND, a copper transporter responsible for copper excretion into bile. We discovered a novel form of sheep WND designated WNDb to distinguish it from the normal form, WNDa. The experiments outlined are designed to understand the function of both proteins in the sheep and their role in copper sequestration.Read moreRead less
Novel roles for importin alpha proteins in the nucleus. The project will provide fundamental new information about how changes in cell function are influenced by importin (IMP) alpha proteins, both through changes in gene transcription and through alterations to intracellular transport. These findings will inform areas of national priority that include Aging Well, Aging Productively with specific regard to cellular stress responses, and A Healthy Start to Life in the context of production of hea ....Novel roles for importin alpha proteins in the nucleus. The project will provide fundamental new information about how changes in cell function are influenced by importin (IMP) alpha proteins, both through changes in gene transcription and through alterations to intracellular transport. These findings will inform areas of national priority that include Aging Well, Aging Productively with specific regard to cellular stress responses, and A Healthy Start to Life in the context of production of healthy, genetically intact sperm. This project draws together an international team to investigate a phenomenon with implications for new understanding of normal developmental processes and the response of cells/tissues to disease conditions.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
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
New approaches to functional and structural genomics. Genome sequencing has revealed complete sets of macromolecules that make up our cells. We now need to learn how these macromolecules work together in a coordinated fashion. The proposed research will lead to the discovery of new biological molecules, interactions and processes essential for the function of cells, identify new therapeutic targets and strategies to combat disease, identify new concepts in bio- and nanotechnology, and train new ....New approaches to functional and structural genomics. Genome sequencing has revealed complete sets of macromolecules that make up our cells. We now need to learn how these macromolecules work together in a coordinated fashion. The proposed research will lead to the discovery of new biological molecules, interactions and processes essential for the function of cells, identify new therapeutic targets and strategies to combat disease, identify new concepts in bio- and nanotechnology, and train new interdisciplinary researchers. It will underpin the National Research Priorities (Frontier Technologies for Building and Transforming Australian Industries, and Promoting and Maintaining Good Health) and help Australia capitalise on a plethora of opportunities for future economic and health benefits.Read moreRead less
Cholesterol-dependent control of plasma membrane lipid rafts. Lipid rafts are recently discovered micro-domains in the plasma membrane that are highly enriched in cholesterol, giving these domains a unique lipid structure. Because of their distinct structure specific proteins partition into these domains so that lipid rafts act as message transduction centres in a variety of cell functions. It is hypothesised that cholesterol is the link between the distinct biophysical parameters of lipid rafts ....Cholesterol-dependent control of plasma membrane lipid rafts. Lipid rafts are recently discovered micro-domains in the plasma membrane that are highly enriched in cholesterol, giving these domains a unique lipid structure. Because of their distinct structure specific proteins partition into these domains so that lipid rafts act as message transduction centres in a variety of cell functions. It is hypothesised that cholesterol is the link between the distinct biophysical parameters of lipid rafts and their function. The aim of this proposal is to understand how cellular cholesterol levels contribute to raft structure and function, thus elevating cholesterol to a regulatory element for lipid raft and their function.Read moreRead less