Double Stranded RNA - The Common Pathogenic Agent In Expanded Repeat Genetically Inherited Neurodegenerative Diseases
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
At least twenty human genetic diseases are due to the expansion of existing repeat sequences beyond a common threshold copy number. While many of these diseases have a common mutation mechanism and share many clinical features the molecular steps critical to their pathogenesis are not yet understood. This project will test the hypothesis that expanded repeat containing RNA, specifically in its double-stranded form, is a common pathogenic agent in many of these diseases.
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.
The Pathogenesis Of Motor Neuron Degeneration Caused By A Triplet Repeat Expansion In The Androgen Receptor Gene.
Funder
National Health and Medical Research Council
Funding Amount
$284,748.00
Summary
Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Ot ....Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Other symptoms include testicular wasting, reduced fertility and breast tissue enlargement. It is currently not known what causes motor nerves to degenerate in Kennedy?s disease. We are endeavouring to investigate the cause of Kennedy?s disease via the generation of a transgenic mouse carrying this mutation. It is only through a studying transgenic mouse affected by this disease can we begin to understand what is happening to nerves to cause them to die, and importantly, how can we prevent them from dying. These studies will also provide crucial information on the effects of sex hormones on nerves. As there is currently no treatment for Kennedy?s disease, an aim of this project is to investigate how we can treat this disease. This will be the first time that we can systemically test potential treatments and work toward preventing the degeneration of these nerves. Kennedy?s disease is related to a number of other neurodegenerative diseases including Huntington?s disease, which are caused by similar genetic mutations. All of these diseases are caused by degeneration of specific nerve cells. Evidence suggests that there may be similar mechanisms involved in all of these diseases. The results of this study will therefore help us to understand a range of diseases and may eventually lead to the development of therapeutic strategies to prevent their debilitating effects.Read moreRead less
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
Identification Of Genes Important In Myeloid And Haemopoietic Development By Genetic Screening In Zebrafish
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of unexpected precision and are leading to new genes with novel specialized ....Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of unexpected precision and are leading to new genes with novel specialized functions. About 50 mutant zebrafish strains exist in which red blood cell development is perturbed - this was easily recognized because the transparency of embryos enabled lack of blood be easily seen. Our new studies aim primarily to recover mutant zebrafish with disorders of white blood cell formation. We have identified methods to recognize failure of white blood cell formation in zebrafish, and will employ these methods to look for inherited disorders that specifically affect white blood cell development in a process called genetic screening. Fish with different sets of randomly mutated genes will be systematically screened to identify those with abnormal white blood cell development. We have tested our approach and identified several mutants affecting white blood cell development. Once these new strains of fish are identified, we will find the genetic lesion responsible for the abnormality in several of the most interesting strains by gene mapping and positional cloning. Hence, the mutant zebrafish identified in the screen will eventually lead to the discovery of new genes important in white blood cell growth and development. The fish themselves will provide insights into the causes of congenital diseases of white blood cells. Since many genes involved in early development are also important in cancer, we believe that newly identified genes will also help understand the causes of abnormal growth of white blood cells in leukaemia.Read moreRead less
Human Genetic Susceptibility To Pulmonary Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$760,432.00
Summary
Tuberculosis (TB) infects about a third of the world population, causing significant disease in 10% of infected individuals. We propose to undertake a genome-wide study to investigate human susceptibility to this devastating disease. Identifying novel gene associations from this study may explain why some people are more vulnerable to TB. Understanding these processes may lead to more effective treatments which is essential for the long term control of disease not only in China, but worldwide
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.