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
Integrated Analysis Of Genome, Epigenome, And Transcriptome Data In Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$417,511.00
Summary
Schizophrenia is a severe psychiatric disorder with a diverse range of symptoms. While the cause is unknown, it is thought to develop from a combination of genetic, epigenetic and environmental risk factors. This study will use genome wide approaches to investigate the relationship between genetic/epigenetic modification of DNA and gene expression in schizophrenia. This study could provide an integrated understanding of the neuropathology of schizophrenia and ultimately lead to better treatment.
The Incidence And Genetics Of The Infantile Epileptic Encephalopathies
Funder
National Health and Medical Research Council
Funding Amount
$175,224.00
Summary
Severe epilepsies with frequent seizures and cognitive impairments in the first 18 months of life are known as ‘infantile epileptic encephalopathies’ (IEE). The cause of IEE is unknown in many patients, although presumed genetic. This study of patients with IEE in Victoria aims to describe the incidence of IEE, and understand the genetic causes of IEE. Understanding the causes of IEE will be the first step towards development of urgently-needed novel therapies for these devastating conditions.
Neourobiology Of Human Epilepsy: Genes, Cellular Mechanisms,network And Whole Brain
Funder
National Health and Medical Research Council
Funding Amount
$17,652,824.00
Summary
The team is comprised of neurologists, molecular geneticists, physiologists and brain imaging specialists and leads the world in the discovery of the genetic causes of epilepsy. They will continue to identify genes underlying epilepsy and study how genetic variations result in development of seizures. Advanced brain imaging will be used to understand the effects of genetic variation on brain structure and function. This study may lead to new diagnostic methods and treatments for epilepsy.
Neuroanatomical Correlates Of Susceptibility In A Model Of Genetic Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$329,275.00
Summary
Genetic generalized epilepsy (GGE) is the most common form of epilepsy, but our understanding of the pathogenesis, in particular anatomical effects of genetic mutations, is incomplete. This project represents the first quantitative study of anatomical changes caused by a human GGE mutation. Pilot data show that the fundamental wiring of the cortex is different in GGE brains with obvious implications for epileptogenesis. This study is expected to inspire improved treatment and diagnosis.
The Genetic And Environmental Determinants Of Amyloid Deposition In Older Individuals: An Amyloid Imaging Study Using The Twin Design
Funder
National Health and Medical Research Council
Funding Amount
$643,267.00
Summary
Alzheimer’s disease is characterised by the deposition of amyloid plaques in the brain. We don’t fully understand how amyloid deposition occurs and what contribution is made by genetic and environmental factors. Amyloid deposition in the brain can now be quantified during life using positron emission tomography. In this study, we will examine brain amyloid in twins, which will determine what proportion of the pathology is attributable to environmental factors that may be modifiable.
Epistatic Genetic Effects On Neuroanatomical Subtypes Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$410,141.00
Summary
Schizophrenia represents a number of clinically distinct syndromes, with a complex mode of inheritance. The delineation of biologically valid subtypes of schizophrenia is necessary to advance our understanding of the genetic basis of these syndromes. This project uses pattern classification techniques to determine subtypes of schizophrenia on the basis of structural brain abnormality across multiple regions, and will examine genetic interactions and differential gene expression associated with t ....Schizophrenia represents a number of clinically distinct syndromes, with a complex mode of inheritance. The delineation of biologically valid subtypes of schizophrenia is necessary to advance our understanding of the genetic basis of these syndromes. This project uses pattern classification techniques to determine subtypes of schizophrenia on the basis of structural brain abnormality across multiple regions, and will examine genetic interactions and differential gene expression associated with these biologically-derived subtypes.Read moreRead less
The Australian Parkinson's Project - Uncovering Genetic Risk Factors For Sporadic PD
Funder
National Health and Medical Research Council
Funding Amount
$768,546.00
Summary
Parkinson s disease (PD) is a progressively disabling movement disorder afflicting many elderly Australians. It is caused by the degeneration of specific nerve cells in the brain that produce certain chemicals and patients suffer from an inability to move fluently (or ultimately at all). At present we do not know what triggers this neurodegeneration, but it is believed that complex interactions between inherited (genetic) and environmental factors contribute significantly to the phenomenon. This ....Parkinson s disease (PD) is a progressively disabling movement disorder afflicting many elderly Australians. It is caused by the degeneration of specific nerve cells in the brain that produce certain chemicals and patients suffer from an inability to move fluently (or ultimately at all). At present we do not know what triggers this neurodegeneration, but it is believed that complex interactions between inherited (genetic) and environmental factors contribute significantly to the phenomenon. This project aims to learn more about these complex interactions and their association with PD. People with PD and unaffected individuals will be recruited from throughout Australia and we will look for specific combinations of genetic, environmental and lifestyle factors that either increase or decrease an individual's risk for PD. This research will identify the most common dominant genetic and environmental influences for PD in Australia, enabling scientists to focus on the most relevant biological pathways to target therapeutically.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