The Integration Of High Level Clinical Medicine, Molecular Genics, And Cutting Edge Neuroimaging
Funder
National Health and Medical Research Council
Funding Amount
$4,000,000.00
Summary
I aim to cement my place as the leading clinical and translational researcher in epilepsy internationally. My research and that of my wider group is focused on the integration of high level clinical medicine, molecular genetics and cutting-edge neuroimaging, which is informed and enhanced by clinically relevant basic neuroscience. This integrative model is unique in the epilepsy field. The Fellowship will give me the opportunity to expand this model and optimally utilize the rapidly developing t ....I aim to cement my place as the leading clinical and translational researcher in epilepsy internationally. My research and that of my wider group is focused on the integration of high level clinical medicine, molecular genetics and cutting-edge neuroimaging, which is informed and enhanced by clinically relevant basic neuroscience. This integrative model is unique in the epilepsy field. The Fellowship will give me the opportunity to expand this model and optimally utilize the rapidly developing technologies in genetics and imaging which are the two most important and productive fields in clinical neuroscience. I am in a unique international position to do this because of the clinical cohorts that I have meticulously collected and characterized over the last two decades, working with the remarkable group of clinical and basic science investigators that form my personal research team, and the wider group that I head, supported by an NHMRC Program Grant. This Fellowship will provide for a major injection of additional core genetic expertise to take us up to the next level necessary to crack the challenging problem of the complex genetics of the epilepsies. I wish to increase the impact and reputation of my wider group as the International Centre for innovative and clinically relevant research in epilepsy. This will enhance the reputation of Australia as a place of excellence in health and medical research.Read moreRead less
Mechanosensitive Channels: Antimicrobials, Channelopathies And Nanovalves For Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$673,953.00
Summary
Liposomal drug delivery systems (LDDS) are one of the most advanced particulate drug carriers in modern medicine. The ultimate goal of this project is to optimize a nanotechnology approach for improved control of therapeutic drug delivery for chemotherapy. The approach is using bacterial mechanosensitive channel MscL designed to act as a molecular nanovalve for localised drug release.
A Novel Ionic Current Contributing To Spasm Of Small Blood Vessels
Funder
National Health and Medical Research Council
Funding Amount
$287,500.00
Summary
Vascular smooth muscle can produce strong constrictions or spasms that can severely limit blood flow. Disorders arising from such spasms include sudden death, neurological deficits, visual and hearing loss or impairment, Raynaud's phenomenon (painful episodic contraction of the fingers and toes) and intestinal necrosis. Common mechanisms are likely to underlie the spasms associated with these disparate disorders. In a recent electrophysiological study of vascular smooth muscle, we discovered a n ....Vascular smooth muscle can produce strong constrictions or spasms that can severely limit blood flow. Disorders arising from such spasms include sudden death, neurological deficits, visual and hearing loss or impairment, Raynaud's phenomenon (painful episodic contraction of the fingers and toes) and intestinal necrosis. Common mechanisms are likely to underlie the spasms associated with these disparate disorders. In a recent electrophysiological study of vascular smooth muscle, we discovered a novel membrane current which we refer to as the plateau current. This current has a strong depolarizing influence that is likely to make a major contribution to the spasms, particularly in arterioles and small arteries which are more dependent on depolarization for contraction. Block of this current is expected to minimize the depolarization and therefore prevent or ameliorate spasm of the vessels. Thus the plateau current represents a new field of therapeutic potential for addressing vascular problems that have significant health implications. However, therapeutic manipulation of the current requires knowledge of its properties. In this project we will determine the biophysical and pharmacological properties of this current using voltage-clamp techniques. We will then use this information to assess its functional significance by recording membrane potential with intracellular microelectrodes simultaneously with contractile activity. We will also compare small vessels obtained from volunteers with or without the vasospastic disorder of Raynaud's phenomenon. Our previous work using these techniques was described in J Physiol as a microelectrode, patch clamp and myograph study of the highest quality and of supreme technical difficulty and scored a Top-Ten hit rate. Since we are the only ones to record the plateau current, we are in a unique position to make significant progress to our understanding of contraction, including spasm, in small blood vessels.Read moreRead less
Mechanism Of Signal Transduction And Receptor Activation In Ligand Gated Ion Channel Receptors
Funder
National Health and Medical Research Council
Funding Amount
$551,560.00
Summary
This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recre ....This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recreational drugs (eg. alcohol, nicotine). They are also targets for development of new therapeutic drugs, such as allosteric modulators of nAChR for memory enhancement, or modulating GlyR to relieve spasticity or chronic pain. The project will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, gives rise to a number of neurological and psychiatric disease states. The ligand gated receptors are also major targets for therapeutic drugs and the information gained in this study may also provide insights into new ways in which drugs could be used to enhance or inhibit synaptic signalling.Read moreRead less
Mechanism Of Signal Transduction And Receptor Activation In Ligand Gated Ion Channel Receptors
Funder
National Health and Medical Research Council
Funding Amount
$456,000.00
Summary
This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. It will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, give rise to a num ....This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. It will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, give rise to a number of neurological and psychiatric disease states. The ligand gated receptors are also major targets for therapeutic drugs and the information gained in this study may also provide insights into new ways in which drugs could be used to enhance or inhibit synaptic signalling.Read moreRead less
Molecular Determinants Of Inhibitory Synaptic Function Studied Using Mutant And Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, ....Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, our aim is to use a range of naturally occuring mice mutants, as well as transgenic mice to modulate the receptor levels and so to examine the role of synaptic function and synaptic dynamics. The outcomes of this project will provide fundamental new knnowledge aimed at understanding how communication in the nervous system works and may suggest ways in which modulation of this information flow could be used to treat disorders of brain function.Read moreRead less