Modulation Of Neurotherapeutic Cell Signalling Pathways By Metallo-complexes As A Treatment For Alzheimers Disease.
Funder
National Health and Medical Research Council
Funding Amount
$653,113.00
Summary
Alzheimer's disease (AD) is an enormous burden on the Australian health care system . We have begun to investigate therapeutic treatments based on triggering protective cell signalling pathways with metal-based compounds. These compounds trigger the activation of a signalling cascade resulting in inhibition of AD-associated symptoms. In this proposal we will further investigate how these compounds modulate specific receptors and cellular kinase activity to protect neurons in the AD brain.
NOVEL THERAPIES FOR ALZHEIMER'S DISEASE BASED ON A-BETA - METAL INTERACTIONS
Funder
National Health and Medical Research Council
Funding Amount
$461,443.00
Summary
The genetic data clearly show that the amyloid protein (A-beta) is central to the brain damage which occurs in Alzheimer's disease (AD). However exogenous or environmental factors involved in regulating its toxic actions are not understood. We have shown that the metals zinc and copper have dramatic effects on the properties of A-beta and that chemicals which alter the amounts of these metals in the brain may be useful in treating the disease. In this project we are investigating the ability of ....The genetic data clearly show that the amyloid protein (A-beta) is central to the brain damage which occurs in Alzheimer's disease (AD). However exogenous or environmental factors involved in regulating its toxic actions are not understood. We have shown that the metals zinc and copper have dramatic effects on the properties of A-beta and that chemicals which alter the amounts of these metals in the brain may be useful in treating the disease. In this project we are investigating the ability of one such compound to affect the metabolism of A-beta in a mouse model of AD.Read moreRead less
The Modulation Of Metals To Improve The Cognitive And Pathological Features Of Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$436,238.00
Summary
This proposal will characterise the effects of a novel therapy for the treatment of Alzheimer's disease. Our preliminary data show that this approach can affect both the onset and progression of the disease, as well as the symptoms that characterise it. Thus, a thorough assessment of these effects and this drug target provides a tangible movement towards a truly effective treatment for Alzheimer's disease.
Copper Homeostasis And APP-induced Neurodegeneration In Drosophila
Funder
National Health and Medical Research Council
Funding Amount
$381,223.00
Summary
Alzheimer s disease, a debilitating neurodegenerative disorder suffered by many of our elderly, is characterised by the presence of abnormal protein accumulations called plaques in the brains of affected patients. Plaques contain amyloid protein and also have high levels of the essential metals copper and zinc. Copper is needed for the formation of these protein aggregations and increases the toxic effects of amyloid, leading to the idea that copper-binding chemicals could be used to treat Alzhe ....Alzheimer s disease, a debilitating neurodegenerative disorder suffered by many of our elderly, is characterised by the presence of abnormal protein accumulations called plaques in the brains of affected patients. Plaques contain amyloid protein and also have high levels of the essential metals copper and zinc. Copper is needed for the formation of these protein aggregations and increases the toxic effects of amyloid, leading to the idea that copper-binding chemicals could be used to treat Alzheimer s disease. However experiments in animal models have produced conflicting results, some suggesting that increased copper levels protect against neuronal damage while others claim the opposite effect. Comparison of these studies is hampered by the different experimental systems used. We will clarify the role of copper in the progression of Alzheimer s disease using a simple insect model, the fly Drosophila melanogaster. Production of amyloid in Drosophila neuronal tissues produces a neurodegenerative effect similar to that seen in human brains, but in a matter of weeks rather than the years required in humans. We will combine production of amyloid with production of copper uptake and export proteins to investigate the effect of changing copper levels. We will also test the effect of increasing copper and other metals in the diet to see whether dietary levels are an important factor in disease progression. Finally, we will use the Drosophila model to test large numbers of metal binding compounds and drugs for ones that slow or halt the neuronal damage caused by amyloid production, identifying potential therapeutics for the treatment of Alzheimer s disease. This work will provide a vital and definitive clarification of the role of copper in the progression of Alzheimer s disease and potentially lead to the development of novel treatments for this disease that is rapidly becoming a major social and economic problem in the developed world.Read moreRead less
By the time a patient first presents with symptoms of Parkinson's disease at the clinic, a large proportion (60-70%) of the cells in a specific part of the brain have been destroyed. This degeneration progresses until, within a few years, most of the cells have died. This project investigates the mechanisms involved in the continued death of cells and a possible new therapy that interrupts the progression. If the aims of this proposal are met, the drug could rapidly go to clinical trial.
Protein Networks Mediating Copper Balance And Their Break-down In Disease.
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Neurological disorders (eg. Alzheimer s, Parkinson s and prion diseases) impose a growing health burden on society. Exciting new therapeutic possibilities stem from the discovery that copper (Cu) plays a central role in the disease process. Our research will help foster a holistic understanding of the protein network regulating copper balance, particularly in the brain, and where it breaks down in disease. Clinical benefits include new targets for diagnosis and treatment of Cu-related diseases.
Impact Of Advanced Glycation On Anti-atherogenic Properties Of High Density Lipoprotein
Funder
National Health and Medical Research Council
Funding Amount
$372,471.00
Summary
Type 2 diabetes is a rapidly growing medical problem in Australia and around the world. Diabetes affects human health through its complications and the cardiovascular complications are a cause for major concern. One of the complications is the effect on plasma lipids: it makes cholesterol carrying particles to accumulate in the blood vessels, causing atherosclerosis. We intend to investigate how diabetes modify these particles making them atherogenic.
The Differential Innervation Of Fat - Potential To Target Visceral Adiposity
Funder
National Health and Medical Research Council
Funding Amount
$486,818.00
Summary
Levels of abdominal fat are closely correlated with metabolic syndrome. We propose experiments to identify unique characteristics (neurotransmitters or receptors) of neurons deep in the brain that project specifically to this type of fat or other less harmful subcutaneous fat. We can then test the functional significance of these unique elements in animal experimets involving gene knockdown or pharmacological approaches to modify their function and test the effect on fat distribution
Improving Successful Long-term Weight Loss By Deactivating The Human Famine Reaction
Funder
National Health and Medical Research Council
Funding Amount
$799,102.00
Summary
There are more than 7 million overweight or obese adults in Australia. With conventional methods of weight loss, only 5% of these people will be able to achieve permanent weight reduction of any significance to health outcomes. This project aims to develop more effective and permanent methods of weight management through comparing effectiveness of continuous versus intermittent dieting; and determining what metabolic, hormonal and behavioural factors predict weight regain.
The Role Of Circadian Rhythm Genes In The Regulation Of Energy Balance And Substrate Metabolism In Muscle And Liver
Funder
National Health and Medical Research Council
Funding Amount
$349,263.00
Summary
Obesity is increasing at an alarming rate worldwide and as the standard of living increases in developing countries such as India and China, the incidence of obesity and its related diseases of diabetes, cardiovascular disease and cancer will become the major health problem of the 21st century. The epidemic of obesity appears to be due to a complex interaction between genetic background and changes in the environment such as reduced physical activity and increased availability and consumption of ....Obesity is increasing at an alarming rate worldwide and as the standard of living increases in developing countries such as India and China, the incidence of obesity and its related diseases of diabetes, cardiovascular disease and cancer will become the major health problem of the 21st century. The epidemic of obesity appears to be due to a complex interaction between genetic background and changes in the environment such as reduced physical activity and increased availability and consumption of high energy food. The accumulation of excess body fat in most individuals is not a precipitous event that occurs over a few days or weeks. Obesity actually occurs insidiously over a period years and is essentially the cumulative result of small differences in daily energy balance. In humans and animals energy balance is subject to diurnal or day-night variations in body temperature, feeding behaviour and physical activity (sleep-wake cycles). Recent research has determined that all tissues in the body have the same genes that regulate circadian (daily) rhythms in the brain. It has also become clear that the expression of these gene cycles over 24 hours in muscle liver and fat tissue the same way that they do in the brain. What is not understood is the extent to which these circadian genes control energy metabolism pathways such as glucose and fat utilisation and storage in liver and muscle. The aim of this grant is to test the effects of changing diet, feeding times and circulating hormones on metabolism and gene expression in muscle and liver to determine the extent to which circadian rhythm genes regulate the normal diurnal metabolism of glucose and fat and whether dysregulation of these systems contributes to metabolic disease.Read moreRead less