Neurons in the two hemispheres of the brain make connections with each other via a large fibre tract called the corpus callosum. In over fifty different human congenital syndromes the corpus callosum fails to form properly. Such syndromes, which include Aicardi syndrome, Andermann syndrome, Shapiro syndrome and Acrocallosal syndrome, can result in mental retardation, seizures, lack of motor coordination and ocular abnormalities in children. Our data on both mouse and human brain development show ....Neurons in the two hemispheres of the brain make connections with each other via a large fibre tract called the corpus callosum. In over fifty different human congenital syndromes the corpus callosum fails to form properly. Such syndromes, which include Aicardi syndrome, Andermann syndrome, Shapiro syndrome and Acrocallosal syndrome, can result in mental retardation, seizures, lack of motor coordination and ocular abnormalities in children. Our data on both mouse and human brain development show that the mouse is an excellent model system for understanding how the brain becomes wired up during development and what may go wrong in these disorders. Here we investigate the role of a family of genes called nuclear factor one (Nfi) genes in brain development. When mutated in mice, members of this gene family, principally Nfia and Nfib, cause severe malformations of the brain. The phenotype inlcudes a failure to form some midline glial populations, the expansion of the cingulate cortex and loss of the corpus callosum. The propoer formation of midline glial populations and the cingulate cortex are essential to callosal fomration and correct brain wiring. Defects in brain wiring in the cingulate cortex during development may underlie disorders such as schizophrenia, bipolar disorder and depression. In this project we will address the mechanism of function underlying the control of brain development by the Nfi genes. The expected outcomes of this research are to identify new mechanisms and genetic pathways critical to the formation of connections between the two sides of the brain and proper formation of the cingulate cortex. These results will improve our understanding of how the brain forms and what mechanisms may be disrupted during development that result in neurological and cognitive deficits in children and adults.Read moreRead less
Sialyltransferase In The Bipolar And Schizophrenic Brain: Examining The Role Of A Novel Generalised Susceptibility Gene
Funder
National Health and Medical Research Council
Funding Amount
$512,627.00
Summary
Bipolar disorder and schizophrenia are two major psychiatric conditions affecting over 800,000 Australians. We have identified a new gene which contributes to increased risk to developing both bipolar disorder and schizophrenia. We will investigate the function of this gene in normal brain development, and how this function is disrupted in individuals with bipolar disorder and schizophrenia. Understanding the biological cause will help us define better treatments for these severe mental illnesse ....Bipolar disorder and schizophrenia are two major psychiatric conditions affecting over 800,000 Australians. We have identified a new gene which contributes to increased risk to developing both bipolar disorder and schizophrenia. We will investigate the function of this gene in normal brain development, and how this function is disrupted in individuals with bipolar disorder and schizophrenia. Understanding the biological cause will help us define better treatments for these severe mental illnesses.Read moreRead less
RNA-based Expanded Repeat Pathogenic Pathway In Neurodegenerative Diseases
Funder
National Health and Medical Research Council
Funding Amount
$595,153.00
Summary
Many important human genetic diseases (incl Huntington’s Disease) are due to a common mutation mechanism with some similarities in clinical outcome (late in life nerve cell loss). For these diseases it is still not known what mechanism is responsible for causing the disease. This is essential in order to delay onset, slow progression or effect cure. We will test a mechanism for disease pathology that we have identified in a simple model organism and seen evidence of its activity in human disease
Cloning And Characterisation Of A Bipolar Disorder Susceptibility Gene On Chromosome 15q
Funder
National Health and Medical Research Council
Funding Amount
$347,621.00
Summary
Bipolar disorder is a severe mood disorder, characterised by aberrant mood swings resulting in periods of mania and depression. We need to define more clearly the biological basis of bipolar disorder to improve diagnosis and treatment. Bipolar disorder is highly heritabile allowing the use of genetics to identify the predisposing genes. Our aim is to identify a bipolar susceptibility gene on chromosome 15 and to understand how this gene contributes to the risk of developing bipolar disorder.
Imaging Genetics In Schizophrenia And Bipolar Disorder: Adjudicating Neurocognitive Endophenotypes
Funder
National Health and Medical Research Council
Funding Amount
$569,873.00
Summary
Schizophrenia and bipolar disorder share some common genes and cognitive deficits, yet manifest differently in terms of symptom expression, illness course, and functional impact. This research tests the assertion that genes implicated as common to these conditions may code for impairments in prefrontal cognitive and sub-cortical emotion processing. We also examine whether between-diagnosis distinctions in these brain responses may be mediated by hypothalamic-pituitary-adrenal axis functioning.
Defining FMR1 And SNRPN Epigenetic Signatures Associated With Neurodevelopmental Disorders
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Fragile X Syndrome and imprinting disorders such as Prader-Willi Syndrome and Angelman Syndrome are characterised by variable penetrance for intellectual disability, motor delay and autism spectrum disorder. This project aims to investigate the prognostic value of using blood-based biomarker tests and sensitive neuroscience informed measures to predict risk and severity of neuropsychological problems in children affected by these disorders.
The Role Of The Ras Signalling Molecule, C3G, In The Interaction Of Neural Precursor Cells And Their Environment
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
Developmental brain disorders affect 1-3% of the population. The mental retardation disease spectrum includes neuronal migration disorders and neural precursor proliferation disorders. We propose to study a molecular mechanism regulating neuronal migration, survival and proliferation. We have identified a protein, C3G, which is essential for three aspects of nervous system development: (A) C3G limits neural precursor cell proliferation. (B) C3G is essential for neuronal survival. (C) C3G is cruc ....Developmental brain disorders affect 1-3% of the population. The mental retardation disease spectrum includes neuronal migration disorders and neural precursor proliferation disorders. We propose to study a molecular mechanism regulating neuronal migration, survival and proliferation. We have identified a protein, C3G, which is essential for three aspects of nervous system development: (A) C3G limits neural precursor cell proliferation. (B) C3G is essential for neuronal survival. (C) C3G is crucial for neuronal migration. C3G acts in a cascade of proteins, known as the Ras signalling pathway, which transmits signals from the extracellular environment into the cell nucleus to elicit appropriate responses of the cell to cues from the outside. We will identify proteins that, together with C3G, affect the important processes of neural precursor proliferation, and neuron survival and migration. This project will fully characterise a key regulatory mechanism of cellular processes crucial to the development of normal intelligence.Read moreRead less
Predictors Of Response To Antidepressants: Utility Of Behavioural, Neuroimaging And Genetics Data
Funder
National Health and Medical Research Council
Funding Amount
$310,071.00
Summary
Major depressive disorder (MDD) is projected to cause the second greatest global burden of disease by 2020, highlighting the urgent need for valid predictors of effective treatment response. Currently, there are no accurate predictors of response to antidepressants in MDD, and successful treatment relies greatly on 'trial and error'. This process is demanding on health resources, and may be a factor in the high suicide rates in depressed patients. Previous research on treatment response has been ....Major depressive disorder (MDD) is projected to cause the second greatest global burden of disease by 2020, highlighting the urgent need for valid predictors of effective treatment response. Currently, there are no accurate predictors of response to antidepressants in MDD, and successful treatment relies greatly on 'trial and error'. This process is demanding on health resources, and may be a factor in the high suicide rates in depressed patients. Previous research on treatment response has been limited by recruitment of small, heterogeneous patient samples, lack of placebo control, and a failure to examine task related activity in brain imaging studies. Perhaps one of the more troubling aspects of research that aims to predict treatment response to antidepressant medications is the use of commonly used outcome measures such as the Hamilton Rating Depression Scale (HAM-D), which were developed long before current classification systems of depression came into use. The US Federal Drug Administration has recently identified what they call a translational gap such that behavioural and biological measures are the most robust for detection of disorders such as depression, yet these measures remain to be translated into clinical tools that can be used to evaluate treatment. The aim of the current study therefore is to determine whether genetic variability is related to treatment outcome as defined by a more objective outcome measure (facial expression perception) using a randomised controlled design. The study will also determine whether brain measures (fMRI, EEG) enhance the prediction of SSRI response to both clinical and behavioural measures, over and above the genetic contribution.Read moreRead less