Liver Cell Transplantation For The Treatment Of Liver Based Metabolic Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$444,143.00
Summary
We propose to investigate the role of liver cell transplantation (LCT) for the therapy of inherited liver-based metabolic diseases using a methylmalonic aciduria (MMA) mouse model. LCT provides an exciting alternative to whole organ transplantation. Initially it was considered liver cells would be immunopriviledged. This has not proven to be the case. Immune modulation will be important. We will also examine immune modulation using antibodies to optimise longterm survival of allogeneic cells.
In Vivo Gene Transfer And Phenotype Correction Of Normal And Urea-cycle Deficient Primary Human Hepatocytes In Chimeric Mouse-human Livers: Towards Gene Therapy For Metabolic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$493,747.00
Summary
Genetic liver disease imposes a major health and economic burden. Existing medical treatments are frequently inadequate, often necessitating liver transplantation which carries its own limitations and risks. Using a gene therapy approach we have achieved life-long cure of mice with OTC-deficiency, a condition with a high risk of disability and death in affected infants. This application focuses on translating this success in mice through to human therapy.
The Role Of Metabolic And Inflammatory Factors In Cognitive Decline And Cerebrovascular Pathology In The Elderly
Funder
National Health and Medical Research Council
Funding Amount
$945,987.00
Summary
Metabolic factors and measures of inflammation in the body have recently been shown to influence mental function and increase the risk of developing age-related disorders such as Alzheimer’s disease. The influence metabolic factors and inflammation have on function of the ageing brain is likely to be determined by complex interplay between many factors, such as physical health, lifestyle, nutrition and our genes. By studying these factors and how they relate to one another in large groups of eld ....Metabolic factors and measures of inflammation in the body have recently been shown to influence mental function and increase the risk of developing age-related disorders such as Alzheimer’s disease. The influence metabolic factors and inflammation have on function of the ageing brain is likely to be determined by complex interplay between many factors, such as physical health, lifestyle, nutrition and our genes. By studying these factors and how they relate to one another in large groups of elderly individuals, we will be able to determine the role these factors play in brain ageing. In addition we will be able to determine an ‘at risk’ profile for elderly individuals for accelerated ageing effects. Identification of this profile is important as it will allow the development of interventions which may prevent or delay the onset of cognitive decline in late life. We plan to study the impact of metabolic and inflammatory factors on brain ageing and in two groups of elderly individuals both of which are currently being studied in detail by our research team. By using these existing groups we will minimize the costs associated with our research, but maximize the research benefit and the benefit to society. Our groups include a large community sample of elderly individuals aged 70-90 years and a large group of elderly twins aged over 65 years. Our use of twins for the study is particularly important as it will help us separate genetic and environmental influences on the measures. We will measure multiple metabolic and inflammatory factors in the body and determine their relationship to detailed tests of cognitive function and to cerebrovascular pathology on brain magnetic resonance imaging. We will look at how these factors relate to one another and which factors are most strongly associated with accelerated ageing. We will be able to follow subjects in each group over a 2 year interval to see which factors most strongly predict change in cognitive function and cerebrovascular pathology over time. Our research is unique in its inclusion of multiple factors which may affect brain ageing, its ability to look in detail at the contribution of genetic influences on metabolic and inflammatory factors, and in our planned follow-up of these individuals.Read moreRead less
Understanding Epigenetic Modification During Oogenesis For Novel Treatments Of Female Infertility
Funder
National Health and Medical Research Council
Funding Amount
$314,644.00
Summary
Infertility affects about 10% of Australian women and the success rates of current infertility treatments are low due to our poor knowledge of eggs development. The numbers of obese and older women trying to conceive are increasing; fertility treatments are even less effective for them. I have generated mouse models to elucidate the pathways regulating egg development. I will study for alterations in these pathways in the mouse models which perfectly mimic the obesity and aging in women.
Non-invasive Gene Delivery For Expression Of Therapeutic Genes In Oligodendrocytes: A New Strategy To Treat Myelin Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$594,393.00
Summary
White matter diseases are debilitating childhood disorders caused by defects in the insulating myelin sheath normally covering and protecting the nerve fibres from damage. There is currently no effective treatment but the delivery of a genetic medicine to the diseased myelin forming cells in the brain could be curative. This project aims at establishing the safe, efficient and non-invasive delivery of therapeutic genes to myelin forming cells as a gene therapy for white matter disorders.
Transforming The Diagnosis Of Mitochondrial Disorders Using High-throughput Sequencing, Functional Prediction And Experimental Validation
Funder
National Health and Medical Research Council
Funding Amount
$670,794.00
Summary
The human genome project sparked enormous improvements in our ability to sequence DNA. “Next Generation” DNA sequencing can potentially sequence an individual’s entire genome in a week and has the ability to transform the diagnosis of inherited diseases but is as yet unproven in a medical genetics context. We will develop and validate the use of Next Generation sequencing to enable the rapid sequencing of over 1000 genes in which mutations cause inherited metabolic diseases.
Sleep-wake Disturbances And Cardio-metabolic Dysfunction In At Risk Dementia: A Novel Pathway In Neurocognitive Decline’
Funder
National Health and Medical Research Council
Funding Amount
$558,305.00
Summary
Age-related sleep and circadian disturbance and cardio-metabolic dysfunction are associated with an increased risk of dementia. This research aims to delineate the pathway in which sleep and circadian disturbances and cardio-metabolic dysfunction promote cognitive decline during the ‘at risk’ dementia phase. This will improve our understanding of key processes in cognitive ageing ultimately leading to the development of targeted intervention programs in the quest to delay the onset of dementia.
How Does Exercise Ameliorate Programming Of Metabolic Dysfunction In Offspring Of Obese Mothers?
Funder
National Health and Medical Research Council
Funding Amount
$524,121.00
Summary
Obesity is a worldwide disease, reflecting an interaction between our environment (diet, physical activity) and genes. We know that a mother's unhealthy diet can predispose offspring to diabetes, and exercise can improve this, but the underlying mechanisms are poorly understood. Here we will examine how exercise can benefit offspring of obese mothers, and test a drug that mimics the effects of exercise. The proposed research will provide insight into ways of reducing the obesity epidemic.
The Transgenerational Epigenetic Inheritance Of Parental Obesity
Funder
National Health and Medical Research Council
Funding Amount
$362,431.00
Summary
The current global epidemic of obesity and diabetes has partly been fuelled by the propagation of these diseases from parent to child across multiple generations. Successful completion of this study will provide hard evidence that there is an inborn but non-genetic component to the risk of obesity and provide insights into the mechanisms by which that risk is created and transmitted from both the mother and the father to the child.
Exploring The Role Of Nitrogen Metabolism, Energy Metabolism And Mitochondrial Function In The Pathophysiological Mechanisms Of Paediatric ME/CFS.
Funder
National Health and Medical Research Council
Funding Amount
$784,064.00
Summary
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease diagnosed by symptoms. Our extensive research has led to a hypothesis that ME/CFS results from toxic by-products of energy production in their cells. This problem can be caused by many unique ways, which could explain the diversity of the ME/CFS patient population. We propose to test this hypothesis with a novel personalised experimental design to simultaneously produce a plethora of new knowledge for the field of ME/CFS.