Functional Characterisation Of A New Regulatory Mechanism For CaMKII At Synapses In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$547,315.00
Summary
CaMKII is an important regulatory molecule in the brain where it plays an essential role in certain forms of learning and memory and in the appropriate development and maturation of neural pathways and undergoes specific changes in animal models of brain ischaemia and epilepsy. Recent evidence has shown that, in nerve cells, the regulation and role of CaMKII is more complicated than previously thought. This project will investigate the roles of a new control mechanism in regulating the function ....CaMKII is an important regulatory molecule in the brain where it plays an essential role in certain forms of learning and memory and in the appropriate development and maturation of neural pathways and undergoes specific changes in animal models of brain ischaemia and epilepsy. Recent evidence has shown that, in nerve cells, the regulation and role of CaMKII is more complicated than previously thought. This project will investigate the roles of a new control mechanism in regulating the function of CaMKII in nerve cells. The experiments will involve an international team of collaborators using cutting edge techniques at the molecular, cellular and whole animal level. This will provide a more complete understanding of how CaMKII influences brain function and allow an assessment of whether CaMKII regulation might be a suitable target for drugs aimed at protecting against the damaging effects of brain injury following stroke or heart attack.Read moreRead less
PATHOGENESIS OF ALZHEIMERS DISEASE AND RELATED DISORDERS: MECHANISM OF TAU PATHOLOGY
Funder
National Health and Medical Research Council
Funding Amount
$295,983.00
Summary
A protein called tau has an essential role in the pathogenesis of Alzheimer's disease (AD), frontotemporal dementia (FTD) and related dementias. We have developed novel transgenic models, which allow us to treat the mice and to abrogate the clinical symptoms. As we have dissected the underlying molecular mechanisms, our ultimate goal is to develop a treatment approach based on these mechanisms and thereby reduce the socio-economic burden of these debilitating diseases.
Targetting Nogo A As A Means To Promote CNS Axonal Regrowth
Funder
National Health and Medical Research Council
Funding Amount
$325,911.00
Summary
Unlike the peripheral nervous system, regenerative nerve fiber growth and structural plasticity are limited in the adult mammalian central nervous system (CNS), following injury. Although lesioned axons can sprout spontaneously, this regeneration attempt is transitory and no significant re-growth occurs over long distances. Consequently, injury to the CNS often leads to permanent disability. In many cases, it has been shown that it is not the absence of growth-promoting molecules in the CNS but ....Unlike the peripheral nervous system, regenerative nerve fiber growth and structural plasticity are limited in the adult mammalian central nervous system (CNS), following injury. Although lesioned axons can sprout spontaneously, this regeneration attempt is transitory and no significant re-growth occurs over long distances. Consequently, injury to the CNS often leads to permanent disability. In many cases, it has been shown that it is not the absence of growth-promoting molecules in the CNS but rather the presence of axon outgrowth inhibitors, including components of both CNS myelin and astroglial scars that limit regeneration. Given that axonal injury is an important pathological determinant of permanent disability in multiple sclerosis (MS), we have recently investigated the role of the CNS neurite outgrowth inhibitor, Nogo A in the development of a chronic form of murine MS-like disease. We showed that targeting Nogo A by active and passive immunization blunts clinical signs, demyelination and axonal damage associated with this model of MS. These results identify Nogo A as an important determinant of the development of autoimmune-mediated demyelination and suggest that its blockage may help to maintain and-or to restore the neuronal integrity of the CNS after autoimmune insult in disease such as MS. The principal goal of this application is to study the mechanism by which blockade of Nogo A improves clinical outcome in disease like MS and to determine whether neurite sprouting accounts for such an improvement. Targeting Nogo A and-or its receptor, has the potential to not only regulate-modulate the process of autoimmune mediated demyelination but could lead to the first therapy ever offered to patients that helps damaged nerves regenerate after axonal injury following neurodegeneration due to insult or disease.Read moreRead less
Targeted Knockdown Of Human SOD1 Genes By Non-viral Gene Delivery To Delay Onset And Progression Of ALS
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
Amyotrophic lateral sclerosis (ALS) is an illness of nerves resulting in a creeping paralysis and death; there is no effective treatment. We have developed immunogenes consisting of an antibody to target specific nerves and a gene that can affect it. Our immunogene will deliver genes that inhibit a mutant protein causing disease in an ALS mouse model. Successful outcomes of this research will be to encourage development of treatments both before and after the disease has developed.
In Parkinson's disease only specific brain cells die, these cells are unusual in that they contain a dark coloured pigment called neuromelanin. The presence of this pigment is thought to play a role in the death of these cells. Evidence from many different diseases has demonstrated that a type of cell damage called oxidative damage is caused by an increase in tissue iron levels. Iron levels are increased in the brains of persons who have died with Parkinson's disease but only in the part of the ....In Parkinson's disease only specific brain cells die, these cells are unusual in that they contain a dark coloured pigment called neuromelanin. The presence of this pigment is thought to play a role in the death of these cells. Evidence from many different diseases has demonstrated that a type of cell damage called oxidative damage is caused by an increase in tissue iron levels. Iron levels are increased in the brains of persons who have died with Parkinson's disease but only in the part of the brain which contains neuromelanin. This increase in iron is thought to lead to oxidative damage and thus cell death in Parkinson's disease. Why iron should be increased specifically in this part of the brain is unknown but it has been shown that neuromelanin binds tissue iron and that the interaction between iron and neuromelanin can result in tissue damage. These events are suggested to underlie the specific vulnerability of the neuromelanin-containing cells in Parkinson's disease. However as yet very little is known about this pigment or how it interacts with iron. This research investigates neuromelanin in the normal brain and in the brain of persons who have died with Parkinson's disease. The project aims to demonstrate how neuromelanin interacts with iron and how neuromelanin, both in the presence and absence of iron, can influence oxidative cell damage. The use of human neuromelanin makes this research unique and it will provide important and novel information regarding the role of this pigment in the aetiology of this devastating disease.Read moreRead less
The Translocator Protein (TSPO) As A Novel Target For The Treatment Of Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$629,260.00
Summary
Alzheimer's disease (AD) is the most prevalent dementia, characterized by progressive loss of memory. An estimated 230,000 Australians currently suffer from AD, causing a huge impact on their families and carers, as well as on national finances. The present therapies are very limited, and there is no cure. Thus, there is a need for novel treatment strategies. We have developed novel drugs that represent an innovative approach to the treatment of AD.
Mechanisms Of Synaptic Vesicle Endocytosis Revealed By Its Regulatory Phosphoproteome
Funder
National Health and Medical Research Council
Funding Amount
$545,216.00
Summary
The nerve cells in our brains are in constant communication to sustain life. Communication involves electrical stimulation of one nerve cell which then responds by releasing chemical messengers, from vesicles, onto the next cell. Our research focuses on the mechanism of recycling of vesicles. Targeting this mechanism is a way to gain fundamental knowledge of how to intervene medically when communication fails, or when communication needs to be dampened, such as in some neurological diseases.
Mitochondria: Molecular And Cellular Insights Into Their Diverse Contributions To Neuronal Injury
Funder
National Health and Medical Research Council
Funding Amount
$747,927.00
Summary
Mitochondria are components of cells normally providing energy for essential functions and in the energy demanding brain, under stress conditions, mitochondria acts as controllers of cellular decision-making processes leading to neuronal death. Our goal is to understand mitochondrial mechanisms determining how neurones die after various stresses and injury. Using pathological insults relevant to neurological conditions, we shall analyse death molecules and how neurones adapt when threatened.
The Effect Of Alteration Of Glucose Use On Brain Function
Funder
National Health and Medical Research Council
Funding Amount
$131,731.00
Summary
Glucose has long been accepted as the mandatory fuel for the brain although it is not fully understood why this is so. Impairment of the glucose supply to the brain results in impairment in brain functions, coma and ultimately death. As a result the body possesses rigid regulatory systems to maintain blood glucose levels within set limits. In certain conditions where blood glucose levels frequently drop below normal, the brain compensates by increasing the uptake of glucose into the brain thus k ....Glucose has long been accepted as the mandatory fuel for the brain although it is not fully understood why this is so. Impairment of the glucose supply to the brain results in impairment in brain functions, coma and ultimately death. As a result the body possesses rigid regulatory systems to maintain blood glucose levels within set limits. In certain conditions where blood glucose levels frequently drop below normal, the brain compensates by increasing the uptake of glucose into the brain thus keeping the glucose supply normal despite lower than normal blood glucose concentrations. In these conditions, which include diabetic hypoglycaemia unawareness, anorexia and starvation, the normal hormonal systems warning of low blood glucose are bypassed. However, despite normal glucose supply to the brain, the performance of the brain is still adversely affected. The electrical activity of the brain changes, reaction times slow, and vigilance is decreased. This implies that, despite the brain having a normal supply of glucose, the glucose is being used differently and that these differences affect the functional performance of the brain. The AIMS of this study are to determine: 1. How does the use of glucose vary in the hypoglycaemia unawareness state? 2. How do these variations effect the performance of the brain? The SIGNIFICANCE of this work lies in 1. Increasing our understanding of the role of glucose in the brain, 2. Increasing our understanding of how the brain works, and, 3. Increasing our understanding of why cognitive impairment occurs in disorders such as diabetes, anorexia and starvation and whether this impairment is reversible. 4. Developing application of a relatively new technique, functional magnetic resonance spectroscopy, for use study of biochemical and cognitive brain disorders.Read moreRead less
The Function Of Dynamin Phosphorylation Sites In Synaptic Vesicle Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$794,565.00
Summary
Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when ....Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when endocytosis cannot keep up then exocytosis slows, greatly reducing the function of neurons. A complete block would result in paralysis of brain and muscles. Our team has been revealing the underlying molecular mechanisms of endocytosis in order to better understand diseases of the synapse like schizophrenia, epilepsy and Alzheimer's disease. We discovered that endocytosis is a regulated process at the heart of which is a pair of phosphorylation sites (points of phosphate attachment) in the key protein dynamin I. Our hypothesis is that endocytosis occurs in two forms, fast and slow. We propose to test the idea that proteins that associate with dynamin via the phosphorylation sites determine whether the fast or slow mode is used. Additionally, we propose that the first phosphorylation site is the trigger for endocytosis, while the second serves to recruit reserve supplies of dynamin to support the slow mode when it's required. A better understanding of Dyn and endocytosis is crucial to understanding brain disorders of synaptic transmission and ultimately for developing therapies. For example, a seizure is the uncontrolled firing of neurons. Our overall aim is to understand the control mechanisms of nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy.Read moreRead less