Investigating Drug Treatments For A Machado Joseph Disease Using Transgenic Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$443,425.00
Summary
Machado Joseph disease (MJD) is a hereditary neurodegenerative disease that causes problems with a patient’s co-ordination and movement, leading to paralysis and death. Although the disease affects patients throughout the world, it is most common within Aboriginal communities of Arnhem Land in the Northern Territory. This project seeks to identify a drug treatment for the disease by examining the effect of relevant drugs on zebrafish genetically modified to have the human gene that causes MJD.
Calpeptin, And Related Candidates, For The Treatment Of Machado Joseph Disease
Funder
National Health and Medical Research Council
Funding Amount
$888,040.00
Summary
Machado Joseph Disease (MJD) is a neurodegenerative disease that causes impaired movement and progressive paralysis, leading to patient death. MJD is inherited within families, including a high number of Indigenous families of northeast Arnhem Land. We have identified a possible treatment for MJD that has positive effects on a small animal model of the disease (zebrafish carrying the human MJD gene). We plan to test this treatment further with the aim of developing a treatment for MJD patients.
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.
A Systems Biology Approach To Elucidate Common Principles And Mechanisms Underlying Triplet Repeat Expansion Associated Genetic Defects
Funder
National Health and Medical Research Council
Funding Amount
$1,033,615.00
Summary
Several human genetic diseases that affect the nervous system occur due to expansions of the DNA repeats in the genome. Here, we use a combination of cutting edge technologies such as systems biology and genomics to uncover the common principles and use them to devise novel therapeutic strategies.
Investigating The Pathogenic Role Of Polyalanine Tract Expansion Mutations In The ARX Homeobox Transcription Factor.
Funder
National Health and Medical Research Council
Funding Amount
$545,619.00
Summary
Intellectual disability is frequent in the population, with as many as 1 in every 50 people in the world directly affected. ARX is one of the most frequent genes mutated in X chromosome-linked intellectual disability. Our study will specifically address the functional impact of these mutations in ARX using cell models relevant to the brain. We will also examine the contribution of other genetic changes to explain the very different symptoms seen in patients with the same gene mutation.
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
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
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.
Investigating The Pathogenic Mechanisms Of Mutations In The ARX Homeobox Transcription Factor
Funder
National Health and Medical Research Council
Funding Amount
$596,222.00
Summary
Intellectual disability is frequent in the population with as many as 1 in every 50 people in the world directly affected. The cost to Australia of intellectual disability is estimated at $14 billion annually. ARX is one of the most frequent genes mutated in X chromosome linked intellectual disability. Our study will specifically address the functional impact of these mutations using cell models relevant to the brain to better understand the pathways and networks required for normal cognition.