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
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
The Role Of The Neuronal Splicing Factor A2BP1 In Autism Spectrum Disorders
Funder
National Health and Medical Research Council
Funding Amount
$396,412.00
Summary
Autism spectrum disorders (ASD) are characterized by language deficits, social impairments and repetitive-restrictive behaviors. ASD is one of the most highly heritable neuropsychiatric conditions, and at the same time genetically very heterogeneous. We have recently shown that shared gene expression abnormalities can be identified in postmortem brain from ASD patients. We now propose to investigate the mechanisms and functional consequences of gene expression abnormalities in ASD.
Truncating Presenilin Mutations And Their Effects On Gamma-secretase Activity, Tau And Beta-catenin
Funder
National Health and Medical Research Council
Funding Amount
$414,005.00
Summary
Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have discovered that, contrary to current thought, mutations that truncate presenilin p ....Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have discovered that, contrary to current thought, mutations that truncate presenilin proteins potently suppress normal presenilin activity. (They are so called, dominant negatives). This means that they are lethal for embryo development and explains why such mutations have never been found in inherited AD. Notably, this discovery could only be made using a subtle form of gene manipulation that is possible in zebrafish embryos. Our work has also established the first assay for the non-apoptotic (non-cell death) function of PSEN2 and has shown that PSEN2 activity is inhibited by truncated PSEN1. This is the first indication of possible interaction between PSEN1 and PSEN2 proteins at normal physiological expression levels. Loss of presenilin activity promotes cancer. Truncated presenilin proteins could be produced by errors in gene transcription (aberrant transcript splicing) common in cancerous cells. This suggests that truncated, dominant negative forms of presenilin produced through aberrant splicing (or mutation in precancerous cells) might be common in tumour formation. The proposed research will define the region of PSEN1 in which truncation leads to dominant negative activity. This will allow further examination of the role of presenilins in the cell signalling pathways involved in AD and cancer. We will also investigate the role that age-related truncation of presenilins in human cells can play in the formation of sporadic AD. This may reveal a common molecular link between the inherited and sporadic forms of this disease.Read moreRead less
Development And Application Of Novel Bioinformatics Approaches To Identify Pathogenetic Mechanisms Underlying Migraine
Funder
National Health and Medical Research Council
Funding Amount
$320,891.00
Summary
Migraine is a public health problem. Although GWAS lead to robust findings, the mechanisms and therapeutic strategies are unknown. This is caused by limited sample size hampering obtaining large number of SNPs by GWAS. Integrating priori knowledge with bioinformatics studies is promising to discover hidden SNPs. Here, I will develop a novel approach to find novel genetic risk loci and genes by integrating comprehensive knowledge on SNPs and genes with GWAS instead of increasing sample.
Identification Of Genes For X-linked Mental Retardation.
Funder
National Health and Medical Research Council
Funding Amount
$675,228.00
Summary
We propose to identify novel heritable causes of intellectual disability using 22 large and well-characterised families from Australia. In these families we have refined the location of the genetic defect to the chromosome X and excluded the contribution of all so far known genes. We will achieve this using the technology of massive parallel sequencing. At the completion of the project we will have identified novel causes of intellectual disability and devised tests to identify them.
Haplotype Variation At The Dopamine Transporter Gene (SLC6A3): Effects On Function, Endo-phenotypes, Cognition And ADHD
Funder
National Health and Medical Research Council
Funding Amount
$585,894.00
Summary
We will investigate variation in the dopamine transporter gene. Variation in this gene will be characterised to a deeper level than has been previously possible using the latest sequencing technology, its biological function will be investigated using biochemical and neuroimaging methods directly in human subjects, and its effects on a clinically important cognitive measure and a common psychiatric condition (attention deficit/hyperactive disorder) will we determined.
Neurologic Effects Of Mutational Load In MELAS Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$505,786.00
Summary
This project will use a new stem cell model to discover what happens to brain cells in patients with the MELAS 3243A>G mutation, a common genetic mutation found in 1-500 Australians. Brain cells will be grown from our stem cell model and used to find out how this mutation causes problems in the affected brain cells. We will find out what happens to the brain when the amount of mutation is reduced in vitro. By understanding what happens, we will be able to design new treatments for this disord ....This project will use a new stem cell model to discover what happens to brain cells in patients with the MELAS 3243A>G mutation, a common genetic mutation found in 1-500 Australians. Brain cells will be grown from our stem cell model and used to find out how this mutation causes problems in the affected brain cells. We will find out what happens to the brain when the amount of mutation is reduced in vitro. By understanding what happens, we will be able to design new treatments for this disorder.Read moreRead less
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.