Structure-function Studies Of Ion Permeation And Selectivity In Recombinant Glycine Receptor Channels
Funder
National Health and Medical Research Council
Funding Amount
$331,300.00
Summary
Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotr ....Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotransmission underlies a range of inherited neurological diseases and already, it has been shown that the human disorder, familial Startle disease (hyperekplexia) occurs because of point mutations that have impaired the permeation and activation of the glycine receptor (GlyR). Similarly, certain epilepsies are now known to be caused by mutations in, or close to, the channel region in the excitatory acetylcholine receptors (AChRs), which affect channel activation and ion permeation. However, because of their very significant structural and functional similarities, information obtained in one member of the LGIC family of receptors has strong potential application to the other members and the GlyR with its simpler structure has certain advantages for investigation. The first aim of this project is to investigate how the molecular biological structure of these ion channels controls permeation, how it affects how different ions are selectively allowed to move through it and how it affects channel activation. A second related aim is to learn more about the process of desensitization of GlyR receptors, whereby a sustained presence of a high concentration of agonist can cause a reduction in receptor response. A third aim is to specifically investigate the mechanisms underlying the mode of molecular disruption resulting from two new Startle disease mutations, which, in addition to their own inherent clinical value, can also give general information about receptor function.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
Group orbits in garmonic analysis and ergodic theory. Researchers from many areas need a type of mathematical analysis which involves the behaviour of a system - which may be a set of data points - under repeated application of some operation or group of operations. The structures arising from this kind of process are known as group orbits. The project gives information about their nature. Two major types of orbits are considered, coming from actions of discrete groups on measure spaces, and fro ....Group orbits in garmonic analysis and ergodic theory. Researchers from many areas need a type of mathematical analysis which involves the behaviour of a system - which may be a set of data points - under repeated application of some operation or group of operations. The structures arising from this kind of process are known as group orbits. The project gives information about their nature. Two major types of orbits are considered, coming from actions of discrete groups on measure spaces, and from smooth actions of Lie groups on manifolds, where powerful geometric methods are available. The project will yield new understandings of entropy, and new approaches to Fourier analysis.Read moreRead less
Ergodic theory and number theory. Recent advances in the theory of measured dynamical systems investigated by the proponents include new versions of entropy, and the study of spectral theory for non-singular systems. These will be further developed in this joint project with the French CNRS. The results are expected to have interesting applications in physics and number theory.
Operator Integrals and Derivatives. The project is a contribution to the study of non-commutative differential and integral calculus. The novelty of the present project lies in the study of smoothness properties of functions whose domains and ranges are spaces of unbounded, non-commuting operators on some Hilbert space. Our general approach will be based on a detailed investigation of properties of double operator integrals, which permit smoothness estimates of operator-functions. It can be expe ....Operator Integrals and Derivatives. The project is a contribution to the study of non-commutative differential and integral calculus. The novelty of the present project lies in the study of smoothness properties of functions whose domains and ranges are spaces of unbounded, non-commuting operators on some Hilbert space. Our general approach will be based on a detailed investigation of properties of double operator integrals, which permit smoothness estimates of operator-functions. It can be expected that the new techniques generated will find further application in areas of mathematical physics and non-commutative geometry related to quantized calculus.
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Entropy and maximal entropy in Markov systems. Entropy is a measure of how well-ordered a system is: chaotic systems have high entropy. Two approaches to entropy are available, via the limiting behaviour of the orbits of points, which yields topological entropy, and via the behaviour of the distributions of measures of partitions, yielding measure-theoretic entropy. The topological entropy is the least upper bound of entropies of all possible measures. We study when there is a measure which real ....Entropy and maximal entropy in Markov systems. Entropy is a measure of how well-ordered a system is: chaotic systems have high entropy. Two approaches to entropy are available, via the limiting behaviour of the orbits of points, which yields topological entropy, and via the behaviour of the distributions of measures of partitions, yielding measure-theoretic entropy. The topological entropy is the least upper bound of entropies of all possible measures. We study when there is a measure which realises this bound, describing the structure of such systems via Markov and Bratteli diagrams. Our methods will be applied to new versions of entropy for non-singular systems. This will assist in the description of chaotic behaviour.Read moreRead less
Symmetries in analysis. Technical research is like an iceberg. The 10% you see in applications is supported by 90% hidden, long-term, sometimes abstruse or theoretical-sounding work. The area of mathematical analysis has, for over 200 years, proved its worth as part of the unseen 90%, giving us such important tools as Fourier analysis, statistical mechanics and quantum mechanics. Australia is known as a world leader in mathematical analysis, and it is important for the country to maintain that e ....Symmetries in analysis. Technical research is like an iceberg. The 10% you see in applications is supported by 90% hidden, long-term, sometimes abstruse or theoretical-sounding work. The area of mathematical analysis has, for over 200 years, proved its worth as part of the unseen 90%, giving us such important tools as Fourier analysis, statistical mechanics and quantum mechanics. Australia is known as a world leader in mathematical analysis, and it is important for the country to maintain that edge in a number of key disciplines, so we can continue to participate in global technological advance. The project has an international focus which will enable that to happen. It will also provide training for the next generation of mathematicians. Read moreRead less
Dynamical systems: theory and practice. Mathematical science has proven a crucial platform for science and technology: it may have a long lead-time to application but its impacts are more profound than glamorous technical developments. Australia has an economic imperative to maintain investment in fundamental mathematics. Dynamical systems underpin a wide range of applications in physics, engineering, information science, finance and economics. This project will improve our capacity to model sy ....Dynamical systems: theory and practice. Mathematical science has proven a crucial platform for science and technology: it may have a long lead-time to application but its impacts are more profound than glamorous technical developments. Australia has an economic imperative to maintain investment in fundamental mathematics. Dynamical systems underpin a wide range of applications in physics, engineering, information science, finance and economics. This project will improve our capacity to model systems and to study their evolution, giving us better predictive power. It will keep Australia in the forefront of international research, providing a basis of expertise not otherwise available to Australian researchers and industry. Read moreRead less
Non-commutative analysis and differential calculus. This project is in an area of central mathematical importance and will lead to important scientific advances that will keep Australia at the forefront internationally in this field of research. There is an emphasis on international networking and we will collaborate with leading researchers in USA and France.
New Insights on Modelling Time Trends with Panel Data: Theory and Practice. This project aims to tackle important challenges in time trend modelling by taking advantage of panel data structures. This project expects to propose flexible models in time trend modelling to retrieve reliable inference. The expected outcomes include innovative econometric models and methods that have a wide range of applications, and are particularly suited for empirical problems within large and complex systems. This ....New Insights on Modelling Time Trends with Panel Data: Theory and Practice. This project aims to tackle important challenges in time trend modelling by taking advantage of panel data structures. This project expects to propose flexible models in time trend modelling to retrieve reliable inference. The expected outcomes include innovative econometric models and methods that have a wide range of applications, and are particularly suited for empirical problems within large and complex systems. This will provide significant benefits to all fields in which data displays any form of trending behaviour. The proposed model is used to evaluate the economic consequences of climate change and global housing market contagion, which provide strong evidence-based insights to the environmental and economic policies in Australia.Read moreRead less