MECHANISMS OF TRANSMITTER SECRETION AT SYMPATHETIC NERVE VARICOSITIES
Funder
National Health and Medical Research Council
Funding Amount
$438,707.00
Summary
The mechanism by which quantal packets of transmitter are secreted from release sites called varicosities on sympathetic nerve terminals can now be taken to the molecular level, given the new techniques which we have introduced to solve this problem. There are two main facets to the problem. The first of these involves the question of how proteins involved in controlling the regulated secretion or exocytosis of the quantal packets of transmitter carry out this function. These proteins (syntaxin, ....The mechanism by which quantal packets of transmitter are secreted from release sites called varicosities on sympathetic nerve terminals can now be taken to the molecular level, given the new techniques which we have introduced to solve this problem. There are two main facets to the problem. The first of these involves the question of how proteins involved in controlling the regulated secretion or exocytosis of the quantal packets of transmitter carry out this function. These proteins (syntaxin, synaptobrevin, SNAP25 and synaptotagmin) together with a calcium channel are complexed with a docked synaptic vesicle containing a quantum of transmitter in a module of secretion appropriately called a secretosome. The leading questions here are to determine if only a single secretosome participates in transmitter release on the arrival of a nerve impulse, whether the number of these secretosomes in a varicosity determines its probability for secretion of a quantum, and fundamentally, how do the proteins within the secretosome cooperate to trigger exocytosis when there is sufficient calcium influx through the secretosome-associated calcium channel following the impulse. The other problem concerns the mechanism of removal of calcium from the varicosity once it has entered through the channels, This calcium can have considerable affects on the extent to which secretosomes participate in secretion with subsequent impulses. Furthermore, this influx of calcium can be modulated for subsequent impulses by transmitter released by the first impulse. The present research will solve these problems, providing a molecular description of secretion from single sympathetic varicosities.Read moreRead less
Sensory Mechanisms In Normal Bladder And In Cystitis
Funder
National Health and Medical Research Council
Funding Amount
$408,861.00
Summary
The function of the lower urinary tract is to store urine and release it at appropriate times. This requires neural circuits in the brain, spinal cord and peripheral ganglia. When the bladder fills, sensory neurones fire and activate these neural circuits to store urine or to empty the bladder. If sensory neurones are too easily excited (a process called sensitisation ) this will lead to clinical disorders, including the common painful bladder syndromes, whose cause is not known (interstitial cy ....The function of the lower urinary tract is to store urine and release it at appropriate times. This requires neural circuits in the brain, spinal cord and peripheral ganglia. When the bladder fills, sensory neurones fire and activate these neural circuits to store urine or to empty the bladder. If sensory neurones are too easily excited (a process called sensitisation ) this will lead to clinical disorders, including the common painful bladder syndromes, whose cause is not known (interstitial cystitis, sensory urgency etc). These are characterised by pelvic pain, urinary urgency, frequency and, in some cases, urge incontinence (loss of urine for no apparent reason) which results from unstable or overactive bladder. Despite a large database of knowledge about the sensory innervation of the bladder, many important gaps still exist. These gaps have restricted the development of new therapies. For example, we have little idea about exactly which functional classes of sensory neurones signal filling of the normal bladder or what different types of information they carry. This is vital information for understanding which neurones are affected in disease states and whether they are all affected in the same way. We have developed new methods that will allow us to identify the major classes of sensory neurones that innervate the bladder, what they respond to and how they are activated. We will also determine whether some classes are preferentially sensitised by inflammation and the most important mechanisms that are likely to underlie this. The significance of this project is that it provides the basic scientific understanding of sensory innervation of the bladder and will identify potential targets for selective pharmacological intervention in common bladder disorders.Read moreRead less
Burden Of Disease: Costing An Effective Package Of Care For Mental Disorders
Funder
National Health and Medical Research Council
Funding Amount
$272,735.00
Summary
The Global Burden of Disease project, a WHO-World Bank-Harvard collaboration, presented an unprecedented picture of global health across the developed and developing world, providing much-needed information for planning health services. Health was measured at the population level, and combined the number of life years lost due to death and disablement to give a total amount of life lost per disorder. One surprise of the project was the importance of mental disorders, accounting for 43% of life y ....The Global Burden of Disease project, a WHO-World Bank-Harvard collaboration, presented an unprecedented picture of global health across the developed and developing world, providing much-needed information for planning health services. Health was measured at the population level, and combined the number of life years lost due to death and disablement to give a total amount of life lost per disorder. One surprise of the project was the importance of mental disorders, accounting for 43% of life years lost due to disability in countries like Australia. Service planning to reduce this burden requires knowledge of cost-effective treatments.This project will trial a method used for combining burden and cost-effectiveness data to design an essential package of services to address the treatment shortfall in mental disorders. This research will assist in our understanding of why burden due to mental disorders persists, and the extent to which current treatment knowledge is able to address this burden within existing budgetary constraints. This will be achieved by: 1) detailing the costs and population outcome of current services in Australia for mental disorders, to determine which disorders are currently adequately treated and which disorders require further intervention, 2) calculating the costs and outcome of best practice interventions from clinical practice guidelines, to understand the extent to which current treatment knowledge can reduce burden due to mental disorders, 3) examining the equity consequences of such a package of ideal interventions, with the understanding that the treatment endpoint is not the same for all disorders. This is a secondary analysis, representing a method for translating existing cost and outcome data for individual treatments into their costs and consequences for health planning at the population level.Read moreRead less
Balance disorders are very common, but particularly in those conditions that involve the brain 'balance centres' are often difficult for doctors to diagnose. When diseases are difficult to diagnose, then recommending helpful treatment is particularly challenging. We will use a group of specialized tests to better understand these balance conditions in order to help patients receive accurate diagnoses and therefore, better treatment.
Balance disorders are very common, but particularly in those conditions that involve the brain 'balance centres' are often difficult for doctors to diagnose. When diseases are difficult to diagnose, then recommending helpful treatment is particularly challenging. We will use a group of specialized tests to better understand these balance conditions in order to help patients receive accurate diagnoses and therefore, better treatment.
Molecular Mediators, Epigenetic Modulators And Therapeutic Targets For Cognitive Disorders
Funder
National Health and Medical Research Council
Funding Amount
$763,845.00
Summary
Brain disorders constitute an enormous, and growing, burden. My research investigates how genes and environment combine to cause disorders of cognition, including dementia, schizophrenia and autism. The research will provide new insights into these disorders, at the level of molecules, cells and behaviour. I will explore how genetic and environmental factors interact, with a focus on mental activity, physical exercise and stress, which affect a range of neurological and psychiatric disorders.
Ocular Motility In Autism And Asperger S Disorder: Dissociation Of Motor Deficits.
Funder
National Health and Medical Research Council
Funding Amount
$131,235.00
Summary
We will use ocular motor technology to investigate motor dysfunction in autism and Asperger's disorder, to advance our understanding of the neurobiological bases of these disorders. This will help clarify whether neural networks are differentially disrupted in these disorders, as our previous clinical research suggests. This dissociation and the subsequent development of an ocular motor clincal screen may improve diagnosis, and potentially treatment, of these devastating conditions.