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
Molecular mechanisms of stem cell self-renewal. Muscle growth and regeneration is critically dependent on its stem cell compartment. We have discovered that the p38 MAPK pathway is essential for stem cell self-renewal in the C2C12 myogenic cell line. This proposal seeks to understand the molecular basis of stem cell self-renewal in skeletal muscles, data that may be applicable to many stem cell systems, and to the enormous promise of stem cell therapies for injury and diseases of the aged. We wi ....Molecular mechanisms of stem cell self-renewal. Muscle growth and regeneration is critically dependent on its stem cell compartment. We have discovered that the p38 MAPK pathway is essential for stem cell self-renewal in the C2C12 myogenic cell line. This proposal seeks to understand the molecular basis of stem cell self-renewal in skeletal muscles, data that may be applicable to many stem cell systems, and to the enormous promise of stem cell therapies for injury and diseases of the aged. We will attempt to alter the balance of stem cell production by enforced p38 expression, and take microarray and proteomics approaches to define stem cell pathways.Read moreRead less
Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investiga ....Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investigation of this protein presents an opportunity for the investigator to work at the forefront in this field adding to Australia's scientific leadership in the area. It also represents an ideal project for post-graduate training and is a collaboration between groups in Brisbane and Melbourne. Read moreRead less
A novel role for SMG-1 protein kinase in stress granule formation and the stress response. Humans are constantly exposed to agents in the environment that threaten the integrity of their cells and increases the risk of cancer and other pathologies. Cells have developed repair mechanisms to cope with damage to their DNA and avoid long term effects. The emphasis in this application is to investigate the mechanisms by which stress affects the transcriptional machinery in the cell. A description of ....A novel role for SMG-1 protein kinase in stress granule formation and the stress response. Humans are constantly exposed to agents in the environment that threaten the integrity of their cells and increases the risk of cancer and other pathologies. Cells have developed repair mechanisms to cope with damage to their DNA and avoid long term effects. The emphasis in this application is to investigate the mechanisms by which stress affects the transcriptional machinery in the cell. A description of the processes involved will assist in understanding how specific disease states arise and will provide a means of devising compounds/drugs to assist the response to stress. Read moreRead less
Developmental Switches: Nuclear Transport and Spermatogenesis. We propose to test the novel hypothesis that changes in the nuclear import machinery are a key facet of cellular differentiation. We will investigate a new paradigm in developmental biology regarding whether differentiation is achieved, or can be directed, by altering transport of macromolecules, such as specific transcription factors, into the nucleus. This project will define changes in the nuclear import machinery that accomp ....Developmental Switches: Nuclear Transport and Spermatogenesis. We propose to test the novel hypothesis that changes in the nuclear import machinery are a key facet of cellular differentiation. We will investigate a new paradigm in developmental biology regarding whether differentiation is achieved, or can be directed, by altering transport of macromolecules, such as specific transcription factors, into the nucleus. This project will define changes in the nuclear import machinery that accompany germ and somatic cell differentiation in the developing and adult mammalian testis. This will be linked to changes in the function of key proteins acting within the nucleus using both in vitro and in vivo approaches.
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Molecular, genetic and cellular analysis of melanisation in human pigmentation. This investigation examines variations in the genes that determine human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasing the general community awareness of ....Molecular, genetic and cellular analysis of melanisation in human pigmentation. This investigation examines variations in the genes that determine human skin pigmentation and are likely to be associated with skin cancer risk. Our research program will form the basis of future diagnostics based on major genes that determine a persons skin type. Current skin cancer prevention strategies rely predominantly on broad spectrum campaigns that are aimed at increasing the general community awareness of the damaging effects of ultraviolet (UV) radiation. A better understanding of the genetic basis of UV-sensitive skin types will greatly enhance the targeting of such skin cancer-prevention campaigns, provide an understanding of changes that occur in skin pathology, and the mechanisms of sun induced tanning.Read moreRead less
Ribonucleic acid (RNA)-binding proteins regulate protein targeting and organelle biosynthesis. We will investigate a new paradigm in biology: the coordination of protein expression in space and time. Detailed knowledge will be gained about proteins that perform important roles in ensuring the proliferative potential of cells an essential aspect of stem cell biology, regenerative medicine and development of cancer. The study combines skills in several aspects of genetics, biochemistry and molecul ....Ribonucleic acid (RNA)-binding proteins regulate protein targeting and organelle biosynthesis. We will investigate a new paradigm in biology: the coordination of protein expression in space and time. Detailed knowledge will be gained about proteins that perform important roles in ensuring the proliferative potential of cells an essential aspect of stem cell biology, regenerative medicine and development of cancer. The study combines skills in several aspects of genetics, biochemistry and molecular cell biology and will therefore provide excellent training opportunities for PhD students and postdoctoral fellows in an internationally highly competitive field of research.Read moreRead less
Novel modes of signalling of serotonin 5-HT2c receptors. This project focuses on a special family of receptor proteins that mediate the actions of the neurochemical, serotonin (5HT), in the human brain. These serotonin receptors are major targets for antidepressant and antipsychotic medications, and also play a role in anxiety, migraine and control of appetite. Despite the important role of serotonin receptors in health and disease, the mechanism of action of many drugs acting on these receptors ....Novel modes of signalling of serotonin 5-HT2c receptors. This project focuses on a special family of receptor proteins that mediate the actions of the neurochemical, serotonin (5HT), in the human brain. These serotonin receptors are major targets for antidepressant and antipsychotic medications, and also play a role in anxiety, migraine and control of appetite. Despite the important role of serotonin receptors in health and disease, the mechanism of action of many drugs acting on these receptors remains unknown. Our project will specifically investigate novel molecular mechanisms associated with serotonin receptor activity that may prove vital in understanding mechanisms of psychiatric illnesses, and how many psychiatric medicines actually work.Read moreRead less
PKC-zeta-dependent Sp1 Phosphorylation: Regulatory Insights using Novel Phospho-Specific Sp1 Antibodies and Peptide Decoys. This project will demonstrate the value of novel phospho-specific Sp1 antibodies and phospho-Sp1 peptide decoys as new molecular tools to provide invaluable insights into the regulatory roles of phosphorylated Sp1 in the control of gene expression, an area poorly defined at the present time. These agents will be used to increase our fundamental understanding of Sp1 activity ....PKC-zeta-dependent Sp1 Phosphorylation: Regulatory Insights using Novel Phospho-Specific Sp1 Antibodies and Peptide Decoys. This project will demonstrate the value of novel phospho-specific Sp1 antibodies and phospho-Sp1 peptide decoys as new molecular tools to provide invaluable insights into the regulatory roles of phosphorylated Sp1 in the control of gene expression, an area poorly defined at the present time. These agents will be used to increase our fundamental understanding of Sp1 activity by identifying physiologic agonists of the PKC-zeta-phospho-Sp1 axis and FasL-dependent apoptosis, interactions of phospho-Sp1 with the authentic FasL promoter and its recruitment of collaborative factors. The commercial exploitation of phospho-specific Sp1 antibodies and phospho-Sp1 peptide decoys will generate economic returns to Australia.Read moreRead less
PKC-zeta-dependent Sp1 phosphorylation: Identification of phosphorylated amino acids, demonstration of functional significance, generation and use of novel phospho-specific Sp1 antibodies. Sp1 is a widely expressed transcription factor that controls the basal expression of virtually every mammalian gene, including that of PDGF-B. We recently reported that PDGF-B expression atypical protein kinase C-zeta phosphorylation of Sp1. Building on these seminal findings, this project will first, delinea ....PKC-zeta-dependent Sp1 phosphorylation: Identification of phosphorylated amino acids, demonstration of functional significance, generation and use of novel phospho-specific Sp1 antibodies. Sp1 is a widely expressed transcription factor that controls the basal expression of virtually every mammalian gene, including that of PDGF-B. We recently reported that PDGF-B expression atypical protein kinase C-zeta phosphorylation of Sp1. Building on these seminal findings, this project will first, delineate the specific amino acid residues in the zinc finger region of Sp1 phosphorylated by PKC-zeta; second, demonstrate the functional importance of these site-specific modifications in the PKC-zeta-Sp1-PDGF-B system and the expression of other genes, and third, generate and use novel antibodies uniquely recognising phosphorylated Sp1 as molecular and diagnostic agents.Read moreRead less