Regulation Of Pre-mRNA And MRNA Processing By The Neuron-specific Hu RNA-binding Proteins
Funder
National Health and Medical Research Council
Funding Amount
$477,750.00
Summary
The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, t ....The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, this activation is just the start of the process to produce an active protein. In higher organisms, these RNA copies almost always contain interruptions called introns, which must be excised from the RNA. Also, protein factors bound to specific RNAs can dictate whether the RNA is used to make protein or not, and these factors can also affect the localisation of the RNA to a specific sub-cellular destination, giving rise to highly localised protein expression. Evidence suggests that neurons are a cell type that rely heavily on mechanisms of RNA regulation. During development neurons become highly polarised, acquiring an axon which can elongate and find distant synaptic targets. While much is known about how axon growth cones respond to various guidance cues, the mechanisms by which the axon is able to translate this guidance cue information into structural changes which allow the growth cone to expand or collapse is largely unexplored. Recent evidence suggests that accurate growth cone guidance is absolutely dependent upon local protein synthesis. The functional corollary of this finding is that axon guidance requires RNA localisation and control of protein synthesis of RNAs in the growth cone. This phenomenon of spatial gene regulation within an individual cell is a central research interest for understanding how the brain functions.Read moreRead less
Development And Refinement Of Neural Connections In The Adult Brain In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$8,061,596.00
Summary
Our group will use innovative approaches such as advanced imaging and cell-sorting and development of animal models to determine how new neurons are generated, how they travel to different parts of the brain and how they integrate into the existing brain circuitry. These discoveries will point to new ways in which to treat brain damage both during ageing and during pathology. Since team members have previously been involved in progressing molecular discovery to clinical trials, we are also in a ....Our group will use innovative approaches such as advanced imaging and cell-sorting and development of animal models to determine how new neurons are generated, how they travel to different parts of the brain and how they integrate into the existing brain circuitry. These discoveries will point to new ways in which to treat brain damage both during ageing and during pathology. Since team members have previously been involved in progressing molecular discovery to clinical trials, we are also in a good position to exploit these discoveries in partnership with the biopharmaceutical industry.Read moreRead less
A Comparative Structural And Functional Cerebral MRI Study Of First Episode Schizophrenia And Long-term Cannabis Use.
Funder
National Health and Medical Research Council
Funding Amount
$373,125.00
Summary
Cannabis is used for its subjective effects that include euphoria, depersonalisation, somnolence, and altered perceptions of temporal contingency.It is a controlled substance yet one quarter of Australian adolescents and seven percent of adults use cannabis regularly. Chronic use of cannibis can impair frontal brain functioning, affecting the capacities for attention, working memory and concentration.These neurocognitive deficits bear striking similarities to those associated with the negative s ....Cannabis is used for its subjective effects that include euphoria, depersonalisation, somnolence, and altered perceptions of temporal contingency.It is a controlled substance yet one quarter of Australian adolescents and seven percent of adults use cannabis regularly. Chronic use of cannibis can impair frontal brain functioning, affecting the capacities for attention, working memory and concentration.These neurocognitive deficits bear striking similarities to those associated with the negative symptom cluster of schizophrenia,which is related to frontal brain dysfunction. The proposed study will be the first of it's kind to apply sophisticated neuroimaging techniques to investigate how long-term adolescent cannabis use effects the structure and function of the brain and to make comparative analyses with the brain changes associated with first episode schizophrenia. We predict that structural brain abnormalities that are consistent in localisation, if not in degree, will be detected in long-term cannabis using and first episode schizophreniaparticipants and that there will be even more profound abnormalities in the first episode schizophrenia cannabis users. We will use the Tower of London (TOL) task to activate certain areas associated with executive functioning (for instance attention, memory, and strategic planning). Here, we expect lower intensity activation of the prefrontal cortex during TOL performance both in the cannabis and first episode schizophrenia groups and that the activation will be lowest of all for the cannabis using first episode schizophrenia group. The methodology to be applied in this study offers a unique opportunity to enhance our understanding of the structural and functional markers of first episode schizophrenia and cannabis use in the neural substrate.Read moreRead less
Mechanisms Contributing To Long-term Neuronal Loss After Hypoxia-ischemia In The Premature Neonate Brain.
Funder
National Health and Medical Research Council
Funding Amount
$432,535.00
Summary
A lack of oxygen (hypoxia) and blood flow to the brain (ischemia) around the time of birth can cause brain injury that perists into adulthood. The burdens on financial, educational and healthcare resources are enormous. We will improve our understanding of what parts of the brain are injured and the mechanisms contributing to on-going brain injury after hypoxia-ischemia.This is important to devise treatments and to provide a healthy start to life for neonates.
Intraocular Transplantation And Regeneration Of Retinofugal Pathways In Rodents
Funder
National Health and Medical Research Council
Funding Amount
$370,937.00
Summary
In the adult human brain and spinal cord there is little or no intrinsic capacity for replacement of lost or dying neurons, and there is minimal spontaneous repair of nerve fibre pathways. Thus traumatic injuries, stroke, or loss of neurons due to chronic degenerative disease result in functional impairments that are usually severe and long-lasting. The personal, social and economic costs associated with these neurological problems are enormous. New ways must be found of protecting and-or replen ....In the adult human brain and spinal cord there is little or no intrinsic capacity for replacement of lost or dying neurons, and there is minimal spontaneous repair of nerve fibre pathways. Thus traumatic injuries, stroke, or loss of neurons due to chronic degenerative disease result in functional impairments that are usually severe and long-lasting. The personal, social and economic costs associated with these neurological problems are enormous. New ways must be found of protecting and-or replenishing nerve cells in damaged CNS gray matter, and new methods are also required to help reconstruct fibre tracts after injury. Using the visual system as an experimental model, the aims of the proposed work are to develop novel transplantation and surgical strategies to: (i) Incorporate new cells into retinae that have been selectively depleted of endogenous neurons (ii) Promote the effective regeneration of large numbers of adult retinal axons through prosthetic peripheral nerve bridging grafts and into host CNS distal to the injury. The results obtained from the first series of studies will not only be of direct relevance to the future treatment of human retinal degenerative disorders, but will also increase our overall understanding of how best to ensure the differentiation and stable integration of different types of transplanted cells within the compromised host CNS. The second series of experiments should lead to an entirely new approach to nerve pathway reconstruction, relevant to both brain and spinal cord injuries. The ultimate aim of this experimental work is to improve the management and treatment of human CNS injury and disease, leading to better functional recovery and rehabilitation.Read moreRead less
Pathogenesis Of Rett Syndrome: Molecular Genetics And Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$437,310.00
Summary
Rett syndrome (RS) is a devastating progressive genetic disorder affecting motor and intellectual development, and occurs almost exclusively in females. It is characterised by normal development for the first 6-12 months of life, followed by developmental regression with the loss of learned purposeful hand function, loss of acquired speech and communicative abilities, sometimes leading to the incorrect diagnosis of autism. It may be the most common cause of progressive mental retardation in girl ....Rett syndrome (RS) is a devastating progressive genetic disorder affecting motor and intellectual development, and occurs almost exclusively in females. It is characterised by normal development for the first 6-12 months of life, followed by developmental regression with the loss of learned purposeful hand function, loss of acquired speech and communicative abilities, sometimes leading to the incorrect diagnosis of autism. It may be the most common cause of progressive mental retardation in girls, with an estimated prevalence in Australia of 1 per 10,000 females under the age of twelve years. Mutations in a gene called MECP2 appears to be the cause of RS in up to 80% of affected girls and women. Now that the gene responsible for many cases of RS has been found, there are many new questions. Do all girls with RS have mutations in the MECP2 gene? Will knowing the exact mutation in the MECP2 gene be of help in predicting how severe the disorder will be in individual patients? Why is it that the brain appears to be primarily affected? Which other genes might play a role in the symptoms seen in RS? Could it be possible to develop specific treatments for RS? This research will address a number of important issues. Firstly, our genetic studies of RS subjects will result in early diagnosis, which is often delayed until after a child turns 5 years of age. Secondly, we are developing mouse models of the human disease, which will put us in a much better position in beginning to understand the biological basis of RS. Early diagnosis may enable the initiation of early treatment strategies in the short term, with the long-term goal of developing specific therapies that may potentially cure the disorder. Finally it will enable accurate genetic counselling for both the immediate and extended family members.Read moreRead less
Mechanisms Of Hypoglycaemic Damage In Developing Brain- A Protective Role For The Insulin-like Growth Factor System
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
The developing brain in the newborn infant or young child is vulnerable to many damaging influences. It is highly dependent on its essential fuel, glucose. Hypoglycemia, or lack of glucose availability, is therefore among the most damaging insults to the young brain, potentially leading to learning difficulties, developmental delay, cerebral palsy or epilepsy. Babies born premature or very small are at risk, as are those exposed to excessive insulin, such as infants of diabetic mothers. Children ....The developing brain in the newborn infant or young child is vulnerable to many damaging influences. It is highly dependent on its essential fuel, glucose. Hypoglycemia, or lack of glucose availability, is therefore among the most damaging insults to the young brain, potentially leading to learning difficulties, developmental delay, cerebral palsy or epilepsy. Babies born premature or very small are at risk, as are those exposed to excessive insulin, such as infants of diabetic mothers. Children with diabetes are also at risk, when their therapy with insulin may at times be excessive, leading to hypoglycaemia and impaired glucose availability for the brain. This proposal is examining at the cellular level the mechanisms involved in loss of brain cells in the face of glucose starvation in these various conditions. We are using several in vitro models where we can grow segments of developing mouse brain or human nerve cells in a dish, compared to studies with mice subjected to low blood glucose (hypoglycemia). After establishing that our laboratory models are representative of the whole animal, we will explore the cellular mechanisms involved in neuronal death following hypoglycaemia, particularly the interaction between the insulin-like growth factor (IGF) and other cell survival genes. We will also examine the possibility that treatment with IGF will reduce the loss of nerves in the brain after an episode of hypoglycemia. This may offer new and effective early treatment for this damaging brain injury in both newborn babies and children with insulin-dependent diabetes.Read moreRead less
In Vivo Analysis Of The Molecular And Neural Mechanism That Underly An Association Of MiRNAs With Mental Disorders
Funder
National Health and Medical Research Council
Funding Amount
$593,778.00
Summary
Genetic studies on autism, schizophrenia, bipolar disorder and major depression suggest that these disorders affect the formation and maintenance of connections between neurons. A group of brain-specific microRNAs, which are regulatory molecules, are predicted to regulate connectivity. Levels of these molecules are found to be abnormal in brains of patients with schizophrenia. This proposal aims to elucidate the function of these microRNAs in the number of neuronal connections, and early motor b ....Genetic studies on autism, schizophrenia, bipolar disorder and major depression suggest that these disorders affect the formation and maintenance of connections between neurons. A group of brain-specific microRNAs, which are regulatory molecules, are predicted to regulate connectivity. Levels of these molecules are found to be abnormal in brains of patients with schizophrenia. This proposal aims to elucidate the function of these microRNAs in the number of neuronal connections, and early motor behavior in transgenic zebrafish.Read moreRead less
High Field Magnetic Resonance Evaluation Of Cerebral And Brainstem Dysfunction In Obstructive Sleep Apnea.
Funder
National Health and Medical Research Council
Funding Amount
$335,175.00
Summary
BACKGROUND: Obstructive Sleep Apnea (OSA) is a condition where repetitive obstruction of the upper airway occurs during sleep. This occurs in susceptible patients when the muscles which normally hold the upper airway open relax with sleep onset. During these interruptions to breathing (apneas) oxygen levels can fall significantly and repetitive awakenings from sleep result. Patients with sleep apnea are often sleepy during the day and experience difficulties with concentration on complex or bori ....BACKGROUND: Obstructive Sleep Apnea (OSA) is a condition where repetitive obstruction of the upper airway occurs during sleep. This occurs in susceptible patients when the muscles which normally hold the upper airway open relax with sleep onset. During these interruptions to breathing (apneas) oxygen levels can fall significantly and repetitive awakenings from sleep result. Patients with sleep apnea are often sleepy during the day and experience difficulties with concentration on complex or boring tasks. Recent improvements in magnetic resonance imaging (MRI) technology allow targeting very small areas of the brain, such as the brainstem, the region of the brain which contols the upper airway muscles. MRI can detect subtle signs of damage to brain cells, and can assess brain activation induced by a task, such as moving the tongue . AIM 1. To identify the presence and patterns of damage to brain cells in patients with OSA by MRI scanning. 2. To examine whether patients with the most severe patterns of injury are also those with the greatest difficulties with sleepiness and concentration. 3. To determine whether these brain abnormalities improve after 6 months of treatment of OSA. 4. To assess activity of the brainstem in wakefulness in OSA patients and compare this to the activity in subjects without OSA. SIGNIFICANCE: This project will advance our understanding of the causes of obstructive sleep apnea. We anticipate it will provide a new method for investigating injury to brain cells in this disease. It will also provide a new means for investigating the causes of OSA and for evaluating novel therapies aimed at enhancing the activity of upper airway muscles and preventing obstruction during sleep.Read moreRead less
Development of normal brain function requires information transfer and integration from outside and within the brain. Normal brain wiring is guided by genetic and environmental cues, whose relative contributions remain controversial. This project investigates the physiological and behavioural consequences of abnormal brain wiring, and the potential for controlled environments and targeted interventions to overcome the deficits. Relevance includes neurotrauma as well as mental illnesses.