The Use Of Soluble Antagonists Of EphA4 In Spinal Cord Injuries
Funder
National Health and Medical Research Council
Funding Amount
$622,361.00
Summary
Permanent and limited recovery of function following spinal cord injury is a direct result of the lack of nerve regrowth through the injury. Our preliminary data suggest that antagonising the effects of EphA4, a protein involved in brain development, leads to substantial functional recovery simultaneous with nerve regrowth. In addition to designing new, more effective blockers of EphA4, we will study the signalling pathways that EphA4 activates to inhibit nerve regrowth.
Heart failure is a severely debilitating condition with a poor prognosis. It is characterized by retention of fluid and high nervous activity especially to the kidneys and the heart. Even with the best current treatment available, patients with heart failure still suffer from abnormally high nerve activity to the further detriment of this condition. The successful completion of this project will provide considerable insight into the role of the brain in the elevated nerve activity in heart failu ....Heart failure is a severely debilitating condition with a poor prognosis. It is characterized by retention of fluid and high nervous activity especially to the kidneys and the heart. Even with the best current treatment available, patients with heart failure still suffer from abnormally high nerve activity to the further detriment of this condition. The successful completion of this project will provide considerable insight into the role of the brain in the elevated nerve activity in heart failure. It will also provide us with a significant understanding of the role in reflex sympathetic nerve regulation of an important brain region known as the hypothalamic paraventricular nucleus (PVN). Our findings will help us understand the nature of the neurotransmitters contributing to the reflex nerve regulation and the specific neurons within the PVN involved. This knowledge could help us to identify novel potential therapeutic targets within the brain to alleviate the problems observed in heart failure.Read moreRead less
Mechanisms Of Cortical Plasticity And Facilitation Of Functional Recovery Following Stroke
Funder
National Health and Medical Research Council
Funding Amount
$427,500.00
Summary
Specific regions of the human brain have been shown to reorganise following damage to the brain or peripheral nerves. This reorganisation is seen in both young and older subjects and is thought to be useful in helping to restore function. For example, following a stroke a patient may, initially, be unable to move one arm. However, in the following weeks and months some function may return. A number of mechanisms may be responsible for this improvement. However, it is likely that at least some of ....Specific regions of the human brain have been shown to reorganise following damage to the brain or peripheral nerves. This reorganisation is seen in both young and older subjects and is thought to be useful in helping to restore function. For example, following a stroke a patient may, initially, be unable to move one arm. However, in the following weeks and months some function may return. A number of mechanisms may be responsible for this improvement. However, it is likely that at least some of the improvement is due to reorganisation within the sensorimotor cortex. Following the stroke the control of the arm may be taken over by adjacent undamaged regions of the brain. This reorganisation allows impressive functional recoveries to occur. We have preliminary evidence to support the idea that patterns of activity generated in peripheral nerves (afferent input) following stroke may be crucial for the development of the organisational changes seen within the brain. We have shown that by applying specific patterns of sensory input we are able to produce organisational changes within the motor cortex of control subjects. Also, we have been able to induce similar changes in stroke patients. These changes have been accompanied by improvements in motor control. These novel and exciting findings support our hypothesis that by applying certain patterns of afferent input to patients following stroke we will be able to facilitate functional recovery by maximising reoganisation within the cortex. In the present project we will establish the organisation patterns in the brain of stroke patients and contrast the findings with control subjects. Secondly we will investigate the potential for facilitating recovery of stroke patients by the application of specific patterns of afferent input. These novel experiments may lead to important therapeutic developments that will benefit the large population of patients suffering strokes.Read moreRead less
Cellular And Molecular Mechanisms Of Neuronal Repair By Olfactory Ensheathing Cells
Funder
National Health and Medical Research Council
Funding Amount
$218,250.00
Summary
Traumatic injury to the human brain and spinal cord often results in permanent disability. A major reason is that nerve fibres which act as cables connecting different parts of the nervous system are injured and fail to regrow. Failure of adequate repair is due to the fact that the central nervous system is a hostile environment, lacking in growth promoting stimuli and instead possessing growth inhibitory properties. One of the experimental methods used to alter this environment is the transplan ....Traumatic injury to the human brain and spinal cord often results in permanent disability. A major reason is that nerve fibres which act as cables connecting different parts of the nervous system are injured and fail to regrow. Failure of adequate repair is due to the fact that the central nervous system is a hostile environment, lacking in growth promoting stimuli and instead possessing growth inhibitory properties. One of the experimental methods used to alter this environment is the transplantation of olfactory ensheathing cells into the injury site. Ensheathing cells normally support the nerve fibres involved in the sense of smell. Tissue culture studies show that these cells produce on their surface specific types of molecules as well as soluble growth factors that could interact with nerve fibres to promote growth. Although experiments in which ensheathing cells have been injected into rat spinal cords, have resulted in varying degrees of recovery, the question of how they are able to do this remains unknown. The study proposed here will use tissue culture and in vivo models to investigate how ensheathing cells interact with their surrounding cells. In particular we will examine how soluble factors and direct membrane contact contribute to the regeneration of nerve fibres. We will also examine the effects that ensheathing cells have on non-neuronal cells such as astrocytes and oligodendrocytes and vice-versa. A significant outcome of this project is new insight into the complex cellular interaction that occurs to bring about repair in the central nervous system. The findings will pave the way for the future development of olfactory ensheathing cells as an effective therapeutic agent of nerve repair. This could also include genetic manipulation of ensheathing cells such that their properties are optimised specifically to promote regrowth of nerve fibres.Read moreRead less
Synaptic Transmission In The Mammalian Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$460,500.00
Summary
In order to properly understand the complex functions of the brain and the abnormalities underlying neurological disorders, we must understand how individual neurons communicate with each other. Communication occurs at specialized contacts, or synapses. An individual neuron may receive tens of thousands of synaptic contacts from hundreds or thousands of other neurons. Despite intensive investigation, the processes which regulate synaptic strength between central neurons are poorly understood. Th ....In order to properly understand the complex functions of the brain and the abnormalities underlying neurological disorders, we must understand how individual neurons communicate with each other. Communication occurs at specialized contacts, or synapses. An individual neuron may receive tens of thousands of synaptic contacts from hundreds or thousands of other neurons. Despite intensive investigation, the processes which regulate synaptic strength between central neurons are poorly understood. The overall aim of this proposal is to understand the basic mechanisms underlying synaptic transmission at excitatory and inhibitory synaptic connections in the mammalian brain. We will investigate specific synaptic connections in the central pathways of the auditory system, because our previous studies have demonstrated a number of key technical advantages in studying these synapses. We will use electrophysiological recording from synaptic terminals and neurons in isolated living slices of the brainstem of mice. We will use imaging techniques and electron-microscopy to examine the structural details of synaptic connections, as structure is thought to play a major role in determining the strength of synaptic transmission. We will also study the structural and functional properties of auditory synaptic connections in congenitally deaf animals. Our recent study comparing normal and congenitally deaf mice has already revealed significant differences. Our results will provide important insights in the regulation of synaptic strength in the central nervous system, and into the regulation of synaptic transmission at central synapses which have developed under conditions of abnormal sensory activation.Read moreRead less
Interactions Between Injured Neurons, Astrocytes And Metallothionein
Funder
National Health and Medical Research Council
Funding Amount
$478,067.00
Summary
We have found that the protein, metallothionein, which protects the brain after injury or during neurodegenerative disease acts in a more complex way than previously thought, including a direct action on injured neurons as well as on the originating cell, astrocytes. Elucidating each component of metallothionein action will help us understand how cells interact in the brain after injury, and excitingly, offers an opportunity to develop an enhanced therapeutic strategy based on this protein.
The Role Of Tau In Experimental Retinal And Optic Nerve Pathology: Relevance To Glaucoma
Funder
National Health and Medical Research Council
Funding Amount
$375,225.00
Summary
Aberrant processing of the axonal protein, tau, is believed to underlie key pathological events in Alzheimer's Disease (AD). Recent data have suggested a link between AD pathology and retinal neuron death in glaucoma. We have further evidence that changes in tau also occur in models of retinal damage. We thus aim to characterise the role of tau in retinal injury models and to relate these findings to glaucoma with a view to having a greater understanding of this disease process.
Roles Of Brain-derived Neurotrophic Factor In The Regulation Of Blood Pressure
Funder
National Health and Medical Research Council
Funding Amount
$299,625.00
Summary
Brain-derived neurotrophic factor (BDNF) is an extraordinary neurotrophin which acts not only as a classical neurotrophic factor to promote neuronal survival and differentiation but also as a neuromodulator to modulate nerve activity. Recently, we found that injection of exogenous BDNF into brain stem triggers a significant increase in blood pressure. The present proposal is to test the hypothesis that BDNF is a physiological neuromodulator regulating blood pressure. The aim of this study is to ....Brain-derived neurotrophic factor (BDNF) is an extraordinary neurotrophin which acts not only as a classical neurotrophic factor to promote neuronal survival and differentiation but also as a neuromodulator to modulate nerve activity. Recently, we found that injection of exogenous BDNF into brain stem triggers a significant increase in blood pressure. The present proposal is to test the hypothesis that BDNF is a physiological neuromodulator regulating blood pressure. The aim of this study is to analyse physiological roles of BDNF in the brains stem and spinal cord in the regulation of nerve activity and blood pressure. The successful execution of the project will significantly enhance our understanding of how blood pressure is controlled by BDNF and nerve activity. The knowledge from this study will form basis for designing new drugs to control high blood pressure.Read moreRead less
Mechanisms Underlying Generation Of Febrile Seizures In Mouse Models Of Human Familial Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$304,559.00
Summary
Febrile Seizures (FS) affect 3% of children aged 0.5 - 6 yrs and have been proposed as an indicator of severe forms of adult generalized epilepsy. Mechanisms underlying FS generation are unknown although studies of Australian families suffering from epilepsy have linked 2 genes to FS. We have generated mice expressing these 2 genes. Aims and Outcomes: to investigate events triggering FS which will provide important insights into why FS occurs in children. (NB: CIA 2 yr career interruption)