The Role Of Central And Peripheral Synaptic Activity In The Developmental Death Of Motoneurons.
Funder
National Health and Medical Research Council
Funding Amount
$463,145.00
Summary
Information processing in the nervous system relies on the effective communication between neurons and their target cells which make up our neuronal circuitry. At the centre of all this is the synapse, the specialized contact between a neuron and its target cell, be it another neuron in the brain or a target organ such as skeletal muscle. Our primary goal is to determine how the formation of synaptic connections during development regulates neuronal survival. In this proposal we have focussed on ....Information processing in the nervous system relies on the effective communication between neurons and their target cells which make up our neuronal circuitry. At the centre of all this is the synapse, the specialized contact between a neuron and its target cell, be it another neuron in the brain or a target organ such as skeletal muscle. Our primary goal is to determine how the formation of synaptic connections during development regulates neuronal survival. In this proposal we have focussed on the neuromotor system as it is a well characterised part of the nervous system. During development, 50% of motoneurons die at a time when they are making contact with skeletal muscle, and when contacts onto motoneurons by other neurons are being established. We believe that the formation of effective synaptic contacts onto motoneurons, as well as connections by motoneurons onto muscle are the key regulators of motoneuron survival. We are in a position to be able to address what regulates motoneuron death; as we have a number of mice which lack key molecules needed for the formation of specialisations that allow neuronal contacts to be made between motor neurons and their muscle, and with other neurons within the spinal cord. By examining the function of motoneurons, counting them and screening for molecular changes in these mice, we will be able to dissect out the mechanism of how a motoneurons' fate is determined during developmental motoneuron death. This research could help in developing strategies aimed at improving neuronal connections to improve neuronal viability. Our research will have important implications for our understanding about the basis of adult neuro-degenerative diseases, such as motor neuron disease and Alzheimer's, which are in part characterised by a molecular breakdown in neuronal connections that ultimately result in neuronal death.Read moreRead less
I am a neuroscientist employing strategies of biochemistry, pathology, pharmacology and developmental biology to examine the mechanisms of neuronal injury contributing to degenerative conditions. My major long-term interest has been excitotoxicity and rec
The Role Of The Ras Signalling Molecule, C3G, In The Interaction Of Neural Precursor Cells And Their Environment
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
Developmental brain disorders affect 1-3% of the population. The mental retardation disease spectrum includes neuronal migration disorders and neural precursor proliferation disorders. We propose to study a molecular mechanism regulating neuronal migration, survival and proliferation. We have identified a protein, C3G, which is essential for three aspects of nervous system development: (A) C3G limits neural precursor cell proliferation. (B) C3G is essential for neuronal survival. (C) C3G is cruc ....Developmental brain disorders affect 1-3% of the population. The mental retardation disease spectrum includes neuronal migration disorders and neural precursor proliferation disorders. We propose to study a molecular mechanism regulating neuronal migration, survival and proliferation. We have identified a protein, C3G, which is essential for three aspects of nervous system development: (A) C3G limits neural precursor cell proliferation. (B) C3G is essential for neuronal survival. (C) C3G is crucial for neuronal migration. C3G acts in a cascade of proteins, known as the Ras signalling pathway, which transmits signals from the extracellular environment into the cell nucleus to elicit appropriate responses of the cell to cues from the outside. We will identify proteins that, together with C3G, affect the important processes of neural precursor proliferation, and neuron survival and migration. This project will fully characterise a key regulatory mechanism of cellular processes crucial to the development of normal intelligence.Read moreRead less
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in general, to maintain the correct number of cells in the body. As such, misregulation of apoptosis is associated with the pathogenesis of a wide array of diseases. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases called caspases, that target many cellular proteins for specific cleavage. The activation of caspases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. If we understand how these regulatory mechanisms operate, we can then formulate strategies that are targeted towards pathologies involving abnormal apoptosis. In this proposal we will use vinegar fly as a model to study the function of caspases in development. We believe that results from this proposal will have several major benefits. Firstly, they will provide important insight into the mechanisms of developmental apoptosis thereby filling many gaps in our current knowledge. Secondly, the study will endeavour to identify new molecules-pathways that lead to caspase activation. Finally, the proposed studies will shed light on the function of caspases in non-apoptotic pathways.Read moreRead less
Role Of Synaptogenesis In Developmental Motoneuron Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$361,650.00
Summary
Naturally occurring cell death is an important and necessary event that shapes the developing embryo. It occurs in all organs of the developing body. In the nervous system about 50% of all neurons die at a time when they are making contact with one another or with their target organs. The underlying mechanisms that drive programmed neuronal cell death are not known. One possibility is that the formation of neuronal contacts (synapses) with other neurons and target cells determines the fate of a ....Naturally occurring cell death is an important and necessary event that shapes the developing embryo. It occurs in all organs of the developing body. In the nervous system about 50% of all neurons die at a time when they are making contact with one another or with their target organs. The underlying mechanisms that drive programmed neuronal cell death are not known. One possibility is that the formation of neuronal contacts (synapses) with other neurons and target cells determines the fate of a neuron. The connections of motor neurons with muscle during this period of developmental neuronal cell death is the best model to examine this phenomenon. In this grant we are in an exciting position to be able to address what causes neuronal cell death, as we have a number of mice that lack key molecules needed for the formation of specializations that allow neuronal contacts to be made between motor neurons and their muscle, and with other neurons within the spinal cord. By examining the function of motor neurons, counting them and screening for molecular changes in these mice, we will be able to dissect out the mechanism of how a motor neurons' fate is determined during the period of programmed cell death. The outcomes of this research will enable us to understand how the nervous system is shaped during development and will increase our knowledge about the basis of adult neurodegenerative diseases. For example, the pathology of Alzheimer's is characterised by a breakdown in neuronal connections that ultimately result in neuronal death and a loss of thought processes (cognition).Read moreRead less
Temporal And Spatial Regulation Of Caspases In Development And Metamorphosis
Funder
National Health and Medical Research Council
Funding Amount
$473,250.00
Summary
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in g ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in general to maintain the correct number of cells in the body. As such, misregulated apoptosis is associated with the pathogenesis of a wide array of diseases such as autoimmune diseases, many forms of cancer and neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), heart disease, ischaemia and other conditions. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases that target many cellular proteins for specific cleavage. The activation of these proteases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. In the present proposal, we aim to study regulation of caspases that are involved in developmental apoptosis. Furthermore, we plan to identify proteins that are responsible for the regulation of caspase activation.Read moreRead less