Advancing The Evidence-base For Childhood Brain Insult: Diagnosis, Assessment And Intervention
Funder
National Health and Medical Research Council
Funding Amount
$575,662.00
Summary
My research has 4 primary objectives, representing major gaps in current knowledge: 1. improve knowledge of recovery and determinants of post-concussive symptoms 2. establish the impact of child brain insult on socio-emotional function and identify contributing factors 3. develop an iPad based tool for socio-emotional function 4. evaluate and disseminate e-heath treatments for child brain insult
Shaken Baby Syndrome: Characterization Of A Model And Evaluation Of Novel Pharmacological Therapies
Funder
National Health and Medical Research Council
Funding Amount
$412,460.00
Summary
Shaken baby syndrome is a form of traumatic brain injury in infants less than 2 years of age. It results in death in 10-40 % of cases, and neurological problems in survivors. No treatment exists largely because there is no well characterized model of the syndrome that replicates the human situation. This study will fully characterize our newly developed model of shaken baby syndrome and examine the effectiveness of a novel interventional strategy targeting brain swelling.
The Role Of Netrin-DCC In The Development Of The Corpus Callosum
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with ove ....During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with over 50 different human congenital syndromes. Thus understanding how the genes and molecules involved in the formation of the corpus callosum function in normal development can provide the basis for our understanding of what goes wrong in ACC. In this proposal we will investigate the role of the axon guidance molecule Netrin1, and its receptor DCC, in development of the corpus callosum in both a mouse model and in humans with malformations of the corpus callosum. Although Netrin1-DCC signalling has traditionally been associated with mechanisms of axon guidance, we hypothesize that these molecules may play a different role, specifically in cellular adhesion and ultimately in the fusion of the two cerebral hemispheres, in a manner that allows the corpus callosum to form. A second role for Netrin1-DCC signalling may be in the guidance of these axons once the midline has fused correctly and we investigate this in Aim 2 of the proposal. Finally, we are collaborating with a paediatric neurologist at UCSF, who has identified several mutations in the DCC gene in patients with ACC. In Aim 3 we test whether these mutations disrupt the function of DCC in callosal axon pathfinding. Understanding how these genes function during development of the brain and how their function may be altered in ACC is crucial to providing a proper diagnosis and prognosis for these patients. Ultimately, understanding more about how these genes function could also lead to prevention of these disorders.Read moreRead less
Encephalitis is a common cause of neurological disability in young adults and adolescents. We have identified a subgroup of encephalitis which is due to the patient's own immune system attacking the brain. Our study will identify the earliest immune responses against the brain in children with encephalitis. Identifying these early immune responses in people with encephalitis will allow early and directed treatments to prevent disability and death in the future.
Understanding the generation of hypothalamic sleep neurons. This Project aims to investigate the mechanisms controlling the formation of the sleep neurons in the hypothalamus. We all sleep, and normal sleep-wake cycles play a central role in our biology. The functional role of these sleep neurons in the mature brain are well established. However, how the neurons are generated during development is very poorly defined. This project aims to address this critical knowledge gap, and will greatly inc ....Understanding the generation of hypothalamic sleep neurons. This Project aims to investigate the mechanisms controlling the formation of the sleep neurons in the hypothalamus. We all sleep, and normal sleep-wake cycles play a central role in our biology. The functional role of these sleep neurons in the mature brain are well established. However, how the neurons are generated during development is very poorly defined. This project aims to address this critical knowledge gap, and will greatly increase our understanding of how the development of this critical aspect of organismal function is orchestrated during development. This project will also develop bioinformatics tools with broad utility within the biosciences field and enhance the capacity for interdisciplinary international collaborations.Read moreRead less
Validation of a New Conceptual Model of ADHD based on Underlying Central Nervous System Dysfunction. ADHD is a debilitating problem that affects 5% of children and approximately half as many adults. ADHD causes substantial problems at school and if untreated, predisposes the individual to increased drug and alcohol use, marital breakdown, criminal prosecution and psychiatric problems in later life. One problem is that we do not fully understand what are the causes of the disorder. This project w ....Validation of a New Conceptual Model of ADHD based on Underlying Central Nervous System Dysfunction. ADHD is a debilitating problem that affects 5% of children and approximately half as many adults. ADHD causes substantial problems at school and if untreated, predisposes the individual to increased drug and alcohol use, marital breakdown, criminal prosecution and psychiatric problems in later life. One problem is that we do not fully understand what are the causes of the disorder. This project will test the validity of several models of brain dysfunction in ADHD which have been influential in the literature, but poorly tested. Through better understanding of the basic underlying problems, more effective intervention can be developed.Read moreRead less
Blood-brain Barrier And White Matter Damage In The Immature Rat Brain Following Systemic Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$353,173.00
Summary
Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infecti ....Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infection and brain damage, one form of which is cerebral palsy, is well established from clinical epidemiological studies, but the biological mechanism of this link is unknown. The CIs' group has recently shown that the condition can be reproduced in neonatal rats at a stage of brain development in the rat that is equivalent to the critical time in human brain development when infection may be associated with brain damage. The CIs' group has shown that an induced inflammatory state similar to a bacterial infection, results in damage to blood vessels in the white matter and is associated with changes in white matter, as occurs in affected babies. The purpose of this study is to understand the nature of the damage to white matter blood vessels and the mechanisms by which materials in blood, which in the normal brain do not pass from the blood to the brain across the blood-brain barrier, are able to do so via the inflammation damaged blood vessels. The study also aims to show whether it is components of the blood entering the brain via the damaged blood vessels that are responsible for the damage to white matter in the immature brain. The outcome should lead to development of ways to improve clinical care of women who acquire infections during pregnancy.Read moreRead less
Targeting Central Inflammation To Combat Obesity And Obesity-related Cognitive Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$470,144.00
Summary
The current obesity epidemic means many of us will suffer from overweight or obesity for at least some of our lives. My findings show obesity can cause inflammation throughout the brain including in regions related to learning and memory. Here I hypothesize that obesity induces long-term changes in the brain’s immune cells, that this can explain why we see susceptibility to cognitive decline in obese individuals, and that we can reverse these negative effects by targeting these immune cells.
The Role Of Reelin-signalling On Cortical Neuron Migration
Funder
National Health and Medical Research Council
Funding Amount
$716,196.00
Summary
Disorders that occur during brain development can lead to abnormal behaviours traits such as anxiety and altered social interactions, plus abnormalities in neuronal function and information processing. The region of the brain responsible for originating the motor, sensory and cognitive functions of a human is the cortex. This brain region is comprised of two major types of neurons that are arranged in a highly organized manner. One captivating aspect of the brain is that during early stages of d ....Disorders that occur during brain development can lead to abnormal behaviours traits such as anxiety and altered social interactions, plus abnormalities in neuronal function and information processing. The region of the brain responsible for originating the motor, sensory and cognitive functions of a human is the cortex. This brain region is comprised of two major types of neurons that are arranged in a highly organized manner. One captivating aspect of the brain is that during early stages of development neurons are generated in one part of the brain and migrate great distances to a final destination. It is therefore necessary during development to have a well-orchestrated, controlled series of events that lead to the correct positioning and association of neurons. The precise functions of many gene products involved in this process are not known. One major advancement in the development of the cortex is the discovery of the protein Reelin which is found in the outermost region of the developing cortex. Mutations in Reelin, in humans, have been implicated in the causation of schizophrenia and mood disorders. These disease states are the result of altered migration of neurons in the cortex. The research proposed in this application is designed to understand the precise process of how two types of neurons migrate and assemble in the cortex. Technology today allows us to visualize, in culture, neurons as they migrate in real-time. This is referred to real time-lapse imaging and allows the researcher the ability to examine how external factors, affect migration of cortical neurons. We will determine how Reelin is involved in this process and our research will elucidate the fundamental process of cortical brain development.Read moreRead less