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
Probing the four photosynthetic membrane protein complexes at work in situ in leaves. This proposal aims at sustainable improvements in plant productivity and photosynthetic adaptation in drastic Australian climates. In photosynthesis, membranes with the four multiprotein complexes use sunlight to make compounds that drive carbon assimilation. Instead of the usual dissection of photosynthetic membranes, this project will develop and refine the applicant's rapid, reliable, non-intrusive technique ....Probing the four photosynthetic membrane protein complexes at work in situ in leaves. This proposal aims at sustainable improvements in plant productivity and photosynthetic adaptation in drastic Australian climates. In photosynthesis, membranes with the four multiprotein complexes use sunlight to make compounds that drive carbon assimilation. Instead of the usual dissection of photosynthetic membranes, this project will develop and refine the applicant's rapid, reliable, non-intrusive techniques to probe the four membrane complexes at work in their native state in leaves. Two portable commercial instruments will potentially emerge from the techniques. This novel non-reductionist approach will identify key limitations to photosynthetic performance under stress, and insights into improvements for primary plant productivity.Read moreRead less
Functional ubiquitination of neuronal voltage-gated sodium channels. Alterations in the electrical properties of excitable cells occur during tissue injury and regeneration as well as many disease states. Preventing or controlling these changes is a key strategic therapeutic aim. It is, however, only through a comprehensive understanding of the molecular mechanisms that regulate cellular excitability that we can identify these therapeutic targets. The major outcome of this project will be a thor ....Functional ubiquitination of neuronal voltage-gated sodium channels. Alterations in the electrical properties of excitable cells occur during tissue injury and regeneration as well as many disease states. Preventing or controlling these changes is a key strategic therapeutic aim. It is, however, only through a comprehensive understanding of the molecular mechanisms that regulate cellular excitability that we can identify these therapeutic targets. The major outcome of this project will be a thorough characterisation of a novel pathway that is potentially crucial in the development, homeostasis and regeneration of the nervous system. Disruption of normal function of this system may underlie the hyperexcitability observed in mannu neurodegenerative conditions.Read moreRead less
SKELETAL MUSCLE: REVERSIBLE TEMEPERATURE-INDUCED UNCOUPLING OF CONTRACTION FROM THE ACTIVATOR Ca2+ AND TUBULAR SYSTEM ROLES IN MUSCLE FUNCTION REGULATION. Skeletal muscles represent the largest organ in the body of vertebrates and are responsible for major functions including maintaining posture and locomotion. Skeletal muscles are also a major source of heat production. The project focuses on temperature-induced effects on the ability of the skeletal muscle to contract in warm blooded animals, ....SKELETAL MUSCLE: REVERSIBLE TEMEPERATURE-INDUCED UNCOUPLING OF CONTRACTION FROM THE ACTIVATOR Ca2+ AND TUBULAR SYSTEM ROLES IN MUSCLE FUNCTION REGULATION. Skeletal muscles represent the largest organ in the body of vertebrates and are responsible for major functions including maintaining posture and locomotion. Skeletal muscles are also a major source of heat production. The project focuses on temperature-induced effects on the ability of the skeletal muscle to contract in warm blooded animals, including marsupials, and on the complex roles played by a cellular structure unique to the muscle fibre, the tubular system, with respect to regulation of muscle function at physiological temperatures. The project will test hypotheses that will have far-reaching implications for muscle physiology, cell biology and evolutionary biology.Read moreRead less
A molecular structure-function investigation of major membrane channels involved in olfactory transduction. Olfactory receptor neurons are extraordinarily-sensitive sensors for detecting minute concentrations of odorant molecules. This project aims to extend our previous studies of these specialised mammalian olfactory cells by using state-of-the art technologies: electrophysiology (patch-clamp) and molecular biology (site-directed-mutagenesis), to investigate how the molecular structure of the ....A molecular structure-function investigation of major membrane channels involved in olfactory transduction. Olfactory receptor neurons are extraordinarily-sensitive sensors for detecting minute concentrations of odorant molecules. This project aims to extend our previous studies of these specialised mammalian olfactory cells by using state-of-the art technologies: electrophysiology (patch-clamp) and molecular biology (site-directed-mutagenesis), to investigate how the molecular structure of their ion channels (selective protein pores) and receptors contribute to the odorant-induced generation of electrical activity, which mediates our sense of smell (olfaction). The project has specific relevance for understanding olfaction, as well as relevance for other sensory systems and other ion channels.Read moreRead less
How triadin and junctin communicate with ryanodine receptors deep within a calcium store to determine skeletal muscle contraction. The project results will provide a platform for muscle relaxants and other drugs that will specifically target either the heart or skeletal muscle and will have applications in the livestock, veterinary and pharmaceutical Industries. The project falls within the National Research Priorities of Promoting and Maintaining Good Health and Frontier Technologies for Buil ....How triadin and junctin communicate with ryanodine receptors deep within a calcium store to determine skeletal muscle contraction. The project results will provide a platform for muscle relaxants and other drugs that will specifically target either the heart or skeletal muscle and will have applications in the livestock, veterinary and pharmaceutical Industries. The project falls within the National Research Priorities of Promoting and Maintaining Good Health and Frontier Technologies for Building and Transforming Australian Industries, as well as the national priority goal of Ageing well, Ageing Productively. The project will be of national benefit in training undergraduate students, PhD students and a postdoctoral fellow in state-of-the-art techniques in an internationally competitive research field.Read moreRead less
REGULATION OF RYANODINE RECEPTOR CALCIUM CHANNELS BY THE CALCIUM BINDING PROTEIN CALSEQUESTRIN. The project is to examine the functional interaction between two proteins in skeletal muscle that are essential for Ca2+ regulation and hence contraction, respiration and movement in all vertebrate species. One protein, the ryanodine receptor, releases calcium from stores inside the muscle cell. The other protein, calsequestrin, binds and sequesters calcium ions. We have recently discovered that th ....REGULATION OF RYANODINE RECEPTOR CALCIUM CHANNELS BY THE CALCIUM BINDING PROTEIN CALSEQUESTRIN. The project is to examine the functional interaction between two proteins in skeletal muscle that are essential for Ca2+ regulation and hence contraction, respiration and movement in all vertebrate species. One protein, the ryanodine receptor, releases calcium from stores inside the muscle cell. The other protein, calsequestrin, binds and sequesters calcium ions. We have recently discovered that the proteins also bind to each other and that calsequestrin regulates Ca2+ release from the stores through the ryanodine receptor ion channel. This regulation is likely to be important in conserving store calcium during stress or fatigue.Read moreRead less
Resurgent Sodium Currents in Peripheral Nerve Axons and Sensory Neurones. This project seeks evidence that unusual gating of sodium channels contributes to the hyperexcitability that results in spontaneous impulse activity in sensory axons. It asks whether axons normally behave as if they have this gating mode, whether it can be induced, whether any such behaviour is more prominent with sensory axons than motor, and whether the current can be measured directly in sensory neurones. The project is ....Resurgent Sodium Currents in Peripheral Nerve Axons and Sensory Neurones. This project seeks evidence that unusual gating of sodium channels contributes to the hyperexcitability that results in spontaneous impulse activity in sensory axons. It asks whether axons normally behave as if they have this gating mode, whether it can be induced, whether any such behaviour is more prominent with sensory axons than motor, and whether the current can be measured directly in sensory neurones. The project is the first to involve correlation of patch-clamp recordings with the behaviour of intact axons. Its outcomes will affect thought about sodium channel behaviour and may alter approaches to disorders of axonal excitability.Read moreRead less