CX3C chemokine signalling in the olfactory epithelium and its role in the self regeneration of the olfactory system. The current proposal will explore new venues in adult neural stem cell research and contribute to the further development of molecular biology and neuroscience research in Western Australia and Australia. The use of neural stem cells holds therapeutic promise for the treatment of a wide variety of neurological conditions, including neurotrauma and stroke. The proposed research wil ....CX3C chemokine signalling in the olfactory epithelium and its role in the self regeneration of the olfactory system. The current proposal will explore new venues in adult neural stem cell research and contribute to the further development of molecular biology and neuroscience research in Western Australia and Australia. The use of neural stem cells holds therapeutic promise for the treatment of a wide variety of neurological conditions, including neurotrauma and stroke. The proposed research will provide new data on the fundamental cellular and molecular events that are required to trigger the birth, differentiation and conditions for growth of new neurons in the adult nervous system. The generation of such insights will be critical for any translational research.
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Interactions between phenome and genome at developing CNS synapses during synaptic refinement. Activity-dependent changes in synaptic transmission are vital to development and function of central neuronal networks. However, the critical factors regulating developmental changes in synaptic signals remain largely unknown. We will correlate functional changes in synaptic responses at glutamate-releasing synapses with changes in glutamate receptor composition at a critical period during developmen ....Interactions between phenome and genome at developing CNS synapses during synaptic refinement. Activity-dependent changes in synaptic transmission are vital to development and function of central neuronal networks. However, the critical factors regulating developmental changes in synaptic signals remain largely unknown. We will correlate functional changes in synaptic responses at glutamate-releasing synapses with changes in glutamate receptor composition at a critical period during development, test whether synaptic activation of receptors is required for these changes and define the pattern of activity-dependent changes in gene expression necessary for developmental changes in synaptic transmission. Understanding this interaction between synaptic phenome and activity-dependent genomic expression will expand our understanding of brain development and function.Read moreRead less
Myofibroblast differentiation: from haemopoietic cells to smooth muscle. Until very recently the ability of adult cells with specific differentiated functions to re-differentiate for another function was thought to be extremely limited. However we have shown that cells ultimately derived from the bone marrow can differentiate into fibroblasts, then into myofibroblasts and then into smooth muscle cells. This project will build on these unique findings and determine the molecular mechanisms cont ....Myofibroblast differentiation: from haemopoietic cells to smooth muscle. Until very recently the ability of adult cells with specific differentiated functions to re-differentiate for another function was thought to be extremely limited. However we have shown that cells ultimately derived from the bone marrow can differentiate into fibroblasts, then into myofibroblasts and then into smooth muscle cells. This project will build on these unique findings and determine the molecular mechanisms controlling this process. We hypothesise that the local environment of a cell is critical and will involve a combination of particular extracellular matrix and growth factors as well as mechanical tension and the presence of other cell types.Read moreRead less
Understanding how the multiple roles of olfactory ensheathing cells guide the growth and regeneration of olfactory axons. The outcomes of this project will increase the understanding of how nerve cells develop and regenerate after injury. The research outcomes and the development of new innovative methodologies as part of the project will be of high significance for the neuroscience research community both within Australia and overseas. The findings will also pave the way for the development of ....Understanding how the multiple roles of olfactory ensheathing cells guide the growth and regeneration of olfactory axons. The outcomes of this project will increase the understanding of how nerve cells develop and regenerate after injury. The research outcomes and the development of new innovative methodologies as part of the project will be of high significance for the neuroscience research community both within Australia and overseas. The findings will also pave the way for the development of novel therapies that promote neuronal regeneration relevant for disorders such as spinal cord injury and Alzheimer's disease, which constitute a large socio-economic burden in Australia. Currently, 400 people contract spinal cord injury every year, corresponding to an annual cost of $1 billion, and more than 500 000 aging people suffer from Alzheimer's disease.Read moreRead less
Combined genetic and cellular analysis of melanisation to study variation in human pigmentation. This investigation examines variations in the genes that are important determinants of 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 increasi ....Combined genetic and cellular analysis of melanisation to study variation in human pigmentation. This investigation examines variations in the genes that are important determinants of 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 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
Parallel genetic and cellular analysis of melanogensis: A new paradigm to study variation in pigmentation. This is the first attempt to characterise the differences in human pigmentation using a combined genetic and cellular analysis of melanogenesis. We have the ability to culture the pigmenting cells of the human epidermis and hair follicles called melanocytes from individuals of defined genotype. This will allow us to correlate mutations in melanosomal proteins with functional defects withi ....Parallel genetic and cellular analysis of melanogensis: A new paradigm to study variation in pigmentation. This is the first attempt to characterise the differences in human pigmentation using a combined genetic and cellular analysis of melanogenesis. We have the ability to culture the pigmenting cells of the human epidermis and hair follicles called melanocytes from individuals of defined genotype. This will allow us to correlate mutations in melanosomal proteins with functional defects within the cells in culture using live cell imaging, electron microscopy and biochemical analysis. This will provide a molecular basis to explain the pigmentary characteristics of individuals allowing prediction and diagnosis of their photosensitivity with important implications for skin cancer risk.Read moreRead less
Control of actin assembly by cell-cell adhesion: molecular effectors and higher order function. Functional cooperation between the actin cytoskeleton and cadherin cell-cell adhesion molecules plays critical roles during development and morphogenesis. This proposal builds on my lab's recent discovery that E-cadherin interacts with and regulates the Arp2/3 actin nucleator complex, a central determinant of actin assembly in cells. We will explore key implications of this finding, concentrating on d ....Control of actin assembly by cell-cell adhesion: molecular effectors and higher order function. Functional cooperation between the actin cytoskeleton and cadherin cell-cell adhesion molecules plays critical roles during development and morphogenesis. This proposal builds on my lab's recent discovery that E-cadherin interacts with and regulates the Arp2/3 actin nucleator complex, a central determinant of actin assembly in cells. We will explore key implications of this finding, concentrating on defining the molecular mechanisms that regulate Arp2/3 and actin assembly in cadherin-based adhesion. Our work combines molecular characterization of regulatory mechanisms and proteomic searches for new regulators, with tests of the higher-order function of this novel process in cell adhesion and recognition.Read moreRead less
Balancing cadherin-actin cooperation: the key regulatory role of Ena/VASP proteins. This project analyses a fundamental mechanism of how cells work together in tissues. Understanding the fundamental mechanisms of how cells work will provide important basic scientific information to enrich the scientific expertise in Australia and its part in the international community, generate insights relevant for understanding human disease and physical degeneration, and support the training of young scienti ....Balancing cadherin-actin cooperation: the key regulatory role of Ena/VASP proteins. This project analyses a fundamental mechanism of how cells work together in tissues. Understanding the fundamental mechanisms of how cells work will provide important basic scientific information to enrich the scientific expertise in Australia and its part in the international community, generate insights relevant for understanding human disease and physical degeneration, and support the training of young scientists in Australia.Read moreRead less
Assessing the physiological roles of ubiquitination in regulating neuronal ion channels, receptors and transporters. Significant alterations in the activity neuronal transporters and receptors occur during tissue injury and regeneration as well as in many neurodegenerative disease states. Modulation of the pathways that control these transporters is an emerging therapeutic target, however, the molecular basis of these control mechanisms remain poorly understood. The outcome of this project will ....Assessing the physiological roles of ubiquitination in regulating neuronal ion channels, receptors and transporters. Significant alterations in the activity neuronal transporters and receptors occur during tissue injury and regeneration as well as in many neurodegenerative disease states. Modulation of the pathways that control these transporters is an emerging therapeutic target, however, the molecular basis of these control mechanisms remain poorly understood. The outcome of this project will be a thorough characterisation of a novel regulatory paradigm in neurons that is likely to be crucial for neuronal development and regeneration, and will potentially provide novel therapeutic targets for various neuronal diseases.Read moreRead less
G-protein coupled receptor-mediated calcium signalling in parasympathetic neurons. External chemical stimuli act on specific cell-surface receptors of neurons resulting in an increase in the intracellular calcium ion concentration which acts as a second messenger to alter neuronal excitability. There are, however, many receptors acting through a number of closely related proteins involving complex intracellular signalling pathways which remain poorly understood. This project uses molecular, elec ....G-protein coupled receptor-mediated calcium signalling in parasympathetic neurons. External chemical stimuli act on specific cell-surface receptors of neurons resulting in an increase in the intracellular calcium ion concentration which acts as a second messenger to alter neuronal excitability. There are, however, many receptors acting through a number of closely related proteins involving complex intracellular signalling pathways which remain poorly understood. This project uses molecular, electrical and fluorescence techniques to elucidate the molecular basis for these interactions by identifying the roles individual proteins play in integrating diverse extracellular stimuli and neuronal excitablility in the peripheral nervous system.Read moreRead less