IMMUNE-MEDIATED INFLAMMATION IN DORSAL ROOT GANGLIA AFTER PERIPHERAL NERVE INJURY AND IN SENSORY NEUROPATHIES
Funder
National Health and Medical Research Council
Funding Amount
$378,300.00
Summary
Damage to the nervous system can occur because of accidental or iatrogenic trauma, toxins, infection, metabolic disorders, and even normal ageing. The consequences can outweigh the direct effects of the injury. Almost all injury to the nervous system results in loss of nerve cells and consequently modified sensation and movement. Nerve damage may also be followed by sensory disturbances, ranging from tingling, numbness and abnormal temperature sensations to spontaneous pain, allodynia (painful s ....Damage to the nervous system can occur because of accidental or iatrogenic trauma, toxins, infection, metabolic disorders, and even normal ageing. The consequences can outweigh the direct effects of the injury. Almost all injury to the nervous system results in loss of nerve cells and consequently modified sensation and movement. Nerve damage may also be followed by sensory disturbances, ranging from tingling, numbness and abnormal temperature sensations to spontaneous pain, allodynia (painful sensations from light touch) or hyperalgesia (increased sensitivity to a damaging stimulus). Some of these symptoms are encountered in older people as they lose sensory neurones. The problems are chronic and most are intractable to drugs. This project will clarify how immune-mediated inflammation of dorsal root (sensory) ganglia (DRGs) contributes to these sequelae. Even the simplest form of neural damage following peripheral nerve injury can produce changes in regions of the nervous system far from the parts directly involved in the injury. Our recent work has described for the first time the involvement of the immune system in triggering changes in DRGs following transection of a distant peripheral nerve in rats. T-cell activation leads to invasion of macrophages and production of proinflammatory cytokines. These substances can activate sensory neurones and may be responsible for progressive neuronal death. Thus we have established a simple system in which we can evaluate the influx of T-cells and macrophages of different kinds into DRGs after injury and other insults. We intend to use this to define the sequence of cellular events involved in recruitment of immune cells and compare it with other experimental interventions known to produce a neuroimmune response in this system. This will identify whether the DRG is a special site for neuroimmune interactions and so should be a target for therapy.Read moreRead less
The Role Of Metabolic And Inflammatory Factors In Cognitive Decline And Cerebrovascular Pathology In The Elderly
Funder
National Health and Medical Research Council
Funding Amount
$945,987.00
Summary
Metabolic factors and measures of inflammation in the body have recently been shown to influence mental function and increase the risk of developing age-related disorders such as Alzheimer’s disease. The influence metabolic factors and inflammation have on function of the ageing brain is likely to be determined by complex interplay between many factors, such as physical health, lifestyle, nutrition and our genes. By studying these factors and how they relate to one another in large groups of eld ....Metabolic factors and measures of inflammation in the body have recently been shown to influence mental function and increase the risk of developing age-related disorders such as Alzheimer’s disease. The influence metabolic factors and inflammation have on function of the ageing brain is likely to be determined by complex interplay between many factors, such as physical health, lifestyle, nutrition and our genes. By studying these factors and how they relate to one another in large groups of elderly individuals, we will be able to determine the role these factors play in brain ageing. In addition we will be able to determine an ‘at risk’ profile for elderly individuals for accelerated ageing effects. Identification of this profile is important as it will allow the development of interventions which may prevent or delay the onset of cognitive decline in late life. We plan to study the impact of metabolic and inflammatory factors on brain ageing and in two groups of elderly individuals both of which are currently being studied in detail by our research team. By using these existing groups we will minimize the costs associated with our research, but maximize the research benefit and the benefit to society. Our groups include a large community sample of elderly individuals aged 70-90 years and a large group of elderly twins aged over 65 years. Our use of twins for the study is particularly important as it will help us separate genetic and environmental influences on the measures. We will measure multiple metabolic and inflammatory factors in the body and determine their relationship to detailed tests of cognitive function and to cerebrovascular pathology on brain magnetic resonance imaging. We will look at how these factors relate to one another and which factors are most strongly associated with accelerated ageing. We will be able to follow subjects in each group over a 2 year interval to see which factors most strongly predict change in cognitive function and cerebrovascular pathology over time. Our research is unique in its inclusion of multiple factors which may affect brain ageing, its ability to look in detail at the contribution of genetic influences on metabolic and inflammatory factors, and in our planned follow-up of these individuals.Read moreRead less
A Novel Marker Of Distressed Neurons In The Hypoxic Brain: Regulation, Function And Potential Clinical Utility.
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
The brain is easily damaged by lack of oxygen (hypoxia). We have recently identified a novel protein called GLAST1b which is expressed in distressed neurons. This protein is a glutamate transporter. Glutamate is implicated as a toxic agent hypoxia. This study will investigate what regulates the expression of GLAST1b, what the consequences of expression are, and whether this marker can be developed as a diagnostic tool for identifying the presence of, and distribution of brain damage.
The Neural Reaction To Injury: Clues To The Cause And Prevention Of Acquired Brain Damage And Alzheimer's Disease.
Funder
National Health and Medical Research Council
Funding Amount
$390,326.00
Summary
The cellular mechanism underlying neuronal degeneration following head trauma and Alzheimer?s disease is not known and represents the major impediment to developing therapeutic strategies to protect nerve cells. This grant application will utilise a variety of modern research methods to determine the key changes in the brain that are associated with the response of nerve cells to physical trauma. These include not only the structural alterations that immediately follow such injury, but the compl ....The cellular mechanism underlying neuronal degeneration following head trauma and Alzheimer?s disease is not known and represents the major impediment to developing therapeutic strategies to protect nerve cells. This grant application will utilise a variety of modern research methods to determine the key changes in the brain that are associated with the response of nerve cells to physical trauma. These include not only the structural alterations that immediately follow such injury, but the complex cellular and gene expression changes that determine the ultimate fate of the cell. Both acquired brain injury and degenerative conditions such as Alzheimer?s disease represent an enormous health, social and economic burden. Furthermore, with predictions that Alzheimer?s disease will increase by 3-4 times by the middle of the next century due to the Oaging? of the population, it is becoming even more crucial to establish effective therapeutic interventions. The animal models investigated in this project can be used to unravel the crucial neuronal alterations associated with head trauma and the early stages of Alzheimer?s disease and, more importantly, may be the key to discovering novel strategies to prevent neuronal degeneration in these conditions.Read moreRead less
Mechanisms Of Central Nervous System Disease Induced By Dysregulated Interferon Signalling
Funder
National Health and Medical Research Council
Funding Amount
$618,165.00
Summary
Interferons are proteins that on one hand have been found to protect cells against infectious agents such as viruses but on the other can cause injury and disease in the brain. In this project the way in which interferons affect the brain to bring about these outcomes will be studied. The results of this work will advance our understanding of how interferons function and may lead to better approaches for combating immune and infectious diseases of the nervous system.
Why Does Early Life Stress Aggravate Limbic Epileptogenesis?
Funder
National Health and Medical Research Council
Funding Amount
$540,116.00
Summary
High rates of anxiety and depression occur in individuals with temporal lobe epilepsy (TLE), the most common form of focal epilepsy in adults. Rats that have experienced early life stress show increased anxiety, decreased seizure thresholds and accelerated epilepsy as adults. We have important leads to mechanisms. The proposed study will better understand the mechanisms connecting early life stress and psychiatric disease to adult TLE, and to test interventions that may counteract these effects.
The presenilin proteins are key components in the development of Alzheimer's disease. Mutations in these proteins can cause early Alzheimer's disease. We will continue our study of the biochemistry and cell biology of these proteins using tools and experimental models that we have already developed. This will provide important information on the mechanism of the disease process and give new leads in the treatment of the disease. The new technologies of genetic screening for presenilin mutations ....The presenilin proteins are key components in the development of Alzheimer's disease. Mutations in these proteins can cause early Alzheimer's disease. We will continue our study of the biochemistry and cell biology of these proteins using tools and experimental models that we have already developed. This will provide important information on the mechanism of the disease process and give new leads in the treatment of the disease. The new technologies of genetic screening for presenilin mutations will be developed and utilized as a National referral base.Read moreRead less
Investigation Of The Mechanisms Involved In Consolidation Of Memory By Beta 3 Adrenoceptoragonists.
Funder
National Health and Medical Research Council
Funding Amount
$241,018.00
Summary
The inability to form new memories is a major and increasingly prevalent health problem for an aging population. In addition to aging, the inability to form new memories is associated with serious medical conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered, but memory does not pass on into permanent storage. We have been able to achieve memor ....The inability to form new memories is a major and increasingly prevalent health problem for an aging population. In addition to aging, the inability to form new memories is associated with serious medical conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered, but memory does not pass on into permanent storage. We have been able to achieve memory consolidation in a particular learning task, which is not normally remembered, by injection of drugs acting on novel receptors (beta 3 adrenoceptors) in the brain of day old chicks. These drugs mimic the action of noradrenaline at beta-3 adrenoceptors. There are a number of ways in which memory consolidation can be enhanced, and we will compare the effects of beta-3 drugs with other potential drugs acting at other types of noradrenaline receptors. One of the actions of beta-3 agonists is related to the uptake of glucose into cells in the brain. We will investigate whether the mechanism of beta-3 enhancement of memory involves the uptake of glucose in brain tissue and studies in cultures of individual cell types will show us which cells are involved. Although this work is done using young chicks, there is no reason to suppose that the basic memory mechanisms at the level of the nerve cell should be different in birds or mammals. There are distinct advantages to using chicks in this research as they can form a long lasting memory for an experience lasting only 10 seconds, and they will discriminate between different colours as part of their learning. This research is aimed at understanding the processes involved in and influencing memory formation. If we are going to develop drugs to alleviate the cognitive problems of old age and more serious cognitive diseases, we need to understand more about the basic mechanisms of memory formation in the normal animal.Read moreRead less