An Analysis Of A Model Of Movement Disorder Lacking D1R Positive Neurons.
Funder
National Health and Medical Research Council
Funding Amount
$346,446.00
Summary
The experiments outlined in this project proposal are aimed at further characterizing a genetically engineered mouse the generation of which was originally funded by the Australian NH and MRC. The mutant mouse suffers from the loss of brain cells in a part of the brain called the striatum. The mouse model will allow us to understand how damage to brain structures cause disabling human neurodegenerative diseases such as Parkinsonism and Huntington's disease. The mouse model is unique as the mice ....The experiments outlined in this project proposal are aimed at further characterizing a genetically engineered mouse the generation of which was originally funded by the Australian NH and MRC. The mutant mouse suffers from the loss of brain cells in a part of the brain called the striatum. The mouse model will allow us to understand how damage to brain structures cause disabling human neurodegenerative diseases such as Parkinsonism and Huntington's disease. The mouse model is unique as the mice suffer from the same type of movement abnormalities which afflict individuals with this spectrum of neurological illnesses. We will look at both structural changes in the brain as well as brain function as defined by the behavioural responses of the damaged brain to drug administration. The experiments also focus on the ultimate correction of the neurological deficits by transplantation of purified nerve cell progenitor cells.Read moreRead less
Gene-environment Interactions And Experience-dependent Plasticity In The Healthy And Diseased Cerebral Cortex
Funder
National Health and Medical Research Council
Funding Amount
$249,250.00
Summary
Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has been inserted into the mouse genome, supporting a role for envi ....Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has been inserted into the mouse genome, supporting a role for environmental factors in disease onset and progression. Following on from our work showing that environmental enrichment delays disease and progression in this mouse model of HD, we are using experimental manipulations of the environment to examine effects on brain degeneration and behaviour. This project aims to investigate gene-environment interactions in HD, focusing on dysfunction of neurons in the cerebral cortex. The combination of behavioural, physiological, anatomical and molecular analysis of HD mice will bring us closer to a comprehensive understanding of HD. This will have implications for the development of new therapies for HD. Our environmental enrichment paradigm may also lead to development of occupational therapy strategies for HD and other neurological disorders. There are at least ten other fatal brain disorders which are caused by the same DNA repeat expansion in other genes. New insights into HD will therefore have implications for the understanding and development of therapeutics for these other DNA repeat expansion brain diseases. Furthermore, another devastating brain disorder which, like HD, involves abnormal protein interactions and dysfunction of the cortex, is Alzheimer's disease. Understanding HD may therefore also have implications for our understanding of Alzheimer's disease. Additionally, analysing control mice in this project will provide new information on mechanisms of plasticity in the normal cortex, which may underlie learning and memory.Read moreRead less
In Vivo Regulation Of The Alzheimers Disease Beta-secretase, BACE1
Funder
National Health and Medical Research Council
Funding Amount
$287,659.00
Summary
Dementia claims 1000 Australians weekly. Alzheimer's disease (AD) is the leading cause of dementia. A hallmark of AD is the presence of beta-amyloid (Ab) plaques in brain. Accumulation of Ab leads to toxicity and cell death. We will use cutting-edge technologies to reduce the level of an enzyme (BACE1) that generates Ab. This study will provide seminal information relating to in vivo regulation of Ab and establish a foundation for our ultimate goal of decreasing BACE1 and Ab in human brain.
Molecular Mechanisms Mediating Experience-dependent Cellular Plasticity And Cognitive Deficits In Huntingtons Disease
Funder
National Health and Medical Research Council
Funding Amount
$550,387.00
Summary
We will use a genetic mouse model of Huntington's disease (HD), to understand how cognitive disorders (dementia) are caused, focusing on cells and molecules within the brain. We will investigate how the HD gene mutation disrupts communication between brain cells (neurons), as well as disrupting production of new cells (via adult neural stem cells). The results of this project will not only have implications for treating HD but also for other diseases involving dementia, such as Alzheimer's.
Relaxin-3 Systems In Brain: Validation Of Neural Targets And Functional Roles
Funder
National Health and Medical Research Council
Funding Amount
$537,579.00
Summary
Our laboratory recently discovered the brain 'transmitter' called 'relaxin-3', and are researching how it affects brain activity and animal physiology and behaviour. Findings suggest that relaxin-3 can modulate memory, responses to stress and other complex behaviours. Identifying the various actions of relaxin-3 in the brain could provide potential new treatments for conditions such as anxiety-depression, cognitive deficits (dementia) and schizophrenia.
Molecular Cell Biology Of HNP22: Role In Alcohol Dependence
Funder
National Health and Medical Research Council
Funding Amount
$346,320.00
Summary
We used a differential screening procedure to detect changes in gene expression in the human alcoholic brain and described a novel gene, which we named hNP22, with increased expression in the superior frontal cortex of the alcoholic cases. This is the first report of a novel alcohol-responsive gene isolated from the human brain. We now propose to further explore the hNP22 gene, its product and its regulation in human brain tissue, and in a variety of experimental systems. We will determine how p ....We used a differential screening procedure to detect changes in gene expression in the human alcoholic brain and described a novel gene, which we named hNP22, with increased expression in the superior frontal cortex of the alcoholic cases. This is the first report of a novel alcohol-responsive gene isolated from the human brain. We now propose to further explore the hNP22 gene, its product and its regulation in human brain tissue, and in a variety of experimental systems. We will determine how protein expression correlates with the level of alcohol consumption. We will use animal and cell culture models to determine the response of the gene to various stimuli. We will express the recombinant protein to determine its function. It is likely that the gene product may be a component in an important signal pathway within neuronal cells and thus may represent a novel target for therapeutic intervention.Read moreRead less
Gene Profiling To Develop A Neuroprotective Strategy In A Large Animals Model Of Following Ischaemic Stroke.
Funder
National Health and Medical Research Council
Funding Amount
$359,897.00
Summary
Stroke affects 15 million people worldwide each year. At present, the diagnosis and treatment of stroke is not optimal. The use of gene profiling may provide us with information that could allow us to more accurately identify individuals at risk of stroke, predict stroke outcome and effectively treat stroke patients. In addition, by using a targeted approach to therapy we have the potential to reduce brain swelling and improve outcome following stroke with neuroprotective agents.
Characterization Ol A Novel Covalently Cross -linked Abeta Peptide Dimer And Its Role In Alzheimers Disease.
Funder
National Health and Medical Research Council
Funding Amount
$553,236.00
Summary
Currently there are limited therapeutic treatments and no cure for Alzheimer's disease (AD). The key protein causing AD is called Abeta. Abeta peptides form dityrosine cross-linked dimers (when 2 peptides join together) and this is thought to be responsible for killing brain cells in AD. Therefore, this proposal will determine the role of Abeta dimers in relation to killing brain cells and the progression of AD through analysis of their biological and biochemical properties.
The Effect Of Metals On Neurofibrillary Tangle Formation
Funder
National Health and Medical Research Council
Funding Amount
$333,313.00
Summary
The majority of studies into Alzheimer's disease (AD) have focussed on two brain lesions- the plaque and neurofibrillary tangle (NFT), which are believed to have a causative role in AD. Our lab has made several seminal discoveries about the role that metals play in the development of plaques. We are now extending this work to evaluate the role of metals in NFT formation. These studies will provide insight into the formation and possible treatments for this primary brain lesion in AD.