Effects Of Latrepirdine On Beta Amyloid Clearance, Aggregation And Neurodegeneration In Alzheimer�s Disease
Funder
National Health and Medical Research Council
Funding Amount
$512,647.00
Summary
Alzheimer's disease (AD) is becoming more common with our growing aged population and currently no treatment exists that halts disease progress. The increasing health costs of AD underscore the need for development of any treatment that will slow or halt AD pathogenesis. By understanding the mechanisms of action of a drug [latrepirdine] that has recently shown some promise in phase II clinical trials, related drugs that are more specific and potent will be developed.
Senataxin, A Novel Protein Involved In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. T ....The human genome is constantly exposed to agents-chemicals that cause DNA damage. Some of these are generated during normal metabolism and are referred to as reactive oxygen species while others comprise damaging sunlight, radiation and a variety of chemical agents. These agents can lead to cancer and a range of pathologies to different tissues including deterioration of brain function. This project is designed to investigate these processes using a specific genetic disorder as a model system. This disorder is called ataxia with oculomotor apraxia type 2 or AOA2. This condition develops in the teenage to early twenties and as the name suggests is characterised by loss of control of gait together with difficulties of eye movement. It is due to reduced function of a particular region of the brain called the cerebellum responsible for controlling movement. We have initial data suggesting that cells from these patients are very sensitive to environmental chemicals and their capacity to carry out repair of damage to DNA is compromised. We will investigate the nature of the defect at the molecular level and establish the function of the protein defective in this syndrome. This information will be important to determining specific therapies for AOA2 patients and may also have relevance to other neurodegenerative disorders.Read moreRead less
The balance between cell division and programmed cell death is crucial for normal development, maintenance of homeostasis, and immune system function. Inappropriately regulated cell death contributes to the pathogenesis of a wide variety of human diseases including neurodegenerative disorders, autoimmune syndromes and several forms of cancer. Death receptors such as Fas and TNFR1 are cell-surface sensors that trigger cellular destruction by apoptosis in response to specific extracellular death s ....The balance between cell division and programmed cell death is crucial for normal development, maintenance of homeostasis, and immune system function. Inappropriately regulated cell death contributes to the pathogenesis of a wide variety of human diseases including neurodegenerative disorders, autoimmune syndromes and several forms of cancer. Death receptors such as Fas and TNFR1 are cell-surface sensors that trigger cellular destruction by apoptosis in response to specific extracellular death signals. Recent studies have demonstrated that the mechanisms of signal transduction through Fas and TNFR1 differ significantly, however, they both require the adaptor protein FADD to induce apoptosis. In this study we will elucidate the molecular basis of the interactions between FADD and its binding partners using biochemical and biophysical studies. This research will improve our understanding of death receptor-induced apoptosis and the differences in signalling mechanisms. A detailed knowledge of these aspects of death receptor signalling is of significance because they represent critical regulatory steps that could be useful for targeted interventions.Read moreRead less
Role Of Amnion Derived Stem Cells In Reducing Lung Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$349,485.00
Summary
Human amniotic epithelial multipotential cells from the term placenta are being studied in a mouse model of pulmonary fibrosis-emphysema to demonstrate their anti-inflammatory, anti-fibrotic, immune-suppresive and lung repair capability. The availability and numbers of these cells from discarded placentas at birth are unlimited and their potential to repair serious lung disease would have strong clinical interest as a new stem cell therapy.
Structural Determinants Underlying High Conductance GABA-A Channels
Funder
National Health and Medical Research Council
Funding Amount
$364,080.00
Summary
Large proteins called GABA-A receptors distributed widely throughout the brain are responsible for inhibition in most neurons. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics, but these valuable drugs still have unwanted side effects. For example, some of them affect cardiac and respiratory function. There is still a need for new, more effec ....Large proteins called GABA-A receptors distributed widely throughout the brain are responsible for inhibition in most neurons. Many general anaesthetics, tranquillisers and anti-epileptic drugs act by modulating GABA-A receptors. Modern surgery would not be possible without rendering patients unconscious with general anaesthetics, but these valuable drugs still have unwanted side effects. For example, some of them affect cardiac and respiratory function. There is still a need for new, more effective general anaesthetics. One in every 200 people in Europe and North America suffers from epilepsy and 3% of the population suffers from anxiety. The leading general anaesthetics, anxiolytic and anti-epileptic drugs currently used, act on GABA-A receptors in the brain. The potential annual market for these drugs has been estimated to be US $2.7 billion. The world market for anaesthetics in 1999 was US $1.6 billion. All were discovered by serendipity. If the molecular site and mode of action of these drugs were understood, it is possible that new, more selective drugs could be discovered. The information gained in this project about GABA-A receptors is expected to be useful in understanding how these receptors work and in developing a new generation of drugs acting on GABA-A receptors. In this project we plan to examine what the functional consequences are and how GABA-A receptors colocalise in the membrane, akin to their physical state in the brain. We will examine the effects of drugs on receptors colocalised in the membrane. We have preliminary evidence suggesting that when GABA-A receptors are close to each other they open together so that their inhibitory response is maximised. Drugs are also able to make GABA-A receptors open in concert. The concept that receptors in the membrane talk to each other has been shown to occur for receptors from different classes but we now have evidence that the same type of receptors i.e. GABA-A receptors, are able to talk to each other.Read moreRead less
NR1F (ROR) Nuclear Hormone Receptors And Metabolism: Insights Into The Control Of Lipid Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
ROR is a member of a gene family, that regulates reproduction, endocrine physiology, and metabolism, and are important in human health. ROR function remains illusive. However, it is expressed in liver, fat and muscle, tissues that (i) modulate blood lipids, insulin sensitivity and energy balance, and (ii) have an important role in diabetes and obesity. Understanding ROR function in metabolism provides the opportunity for the discovery of new pathways that ameliorate metabolic disease.
Molecular Regulation Of Metabolism And Body Composition By Ski Via Crosstalk With Nuclear Hormone Receptor Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$558,441.00
Summary
Obesity is a common and burdensome health problem in the community which leads to diabetes and heart disease. A number of factors, including hormones play important roles in determing risk of obesity. This study proposes to investigate whether the Ski gene which is a regulatory factor for many hormones affects metabolism in transgenic mouse models of altered Ski function. The proposed studies may identify Ski as a target for therapy for obesity and improvement in sketal muscle metabolism.
NR4A Orphan Nuclear Receptor Signalling In Skeletal Muscle: Evidence For Crosstalk With The Beta-adrenergic Pathway.
Funder
National Health and Medical Research Council
Funding Amount
$323,749.00
Summary
The NR4A subgroup of are 'orphan' members of the nuclear hormone receptor (NR) superfamily (that are all implicated in human disease). NRs are hormone-dependent DNA binding proteins that translate nutritional and pathophysiological signals into gene regulation. The importance of this 'drugable' gene family in the context of promoting and maintaining human health is underscored by the diversity of medicinals associated with dysfunctional hormone signalling, in the context of inflammation, diabete ....The NR4A subgroup of are 'orphan' members of the nuclear hormone receptor (NR) superfamily (that are all implicated in human disease). NRs are hormone-dependent DNA binding proteins that translate nutritional and pathophysiological signals into gene regulation. The importance of this 'drugable' gene family in the context of promoting and maintaining human health is underscored by the diversity of medicinals associated with dysfunctional hormone signalling, in the context of inflammation, diabetes, dyslipidemia, and endocrine disorders (e.g ~15% of the top selling therapeutic compounds target NRs). The NR4A subgroup are stress response genes which are induced by a wide range of physiological stimuli and have been implicated in the response to energy excess (over-eating) and diet induced obesity. The NR4A subgroup are expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of the body mass and energy expenditure. This lean tissue is a major site of fat oxidation, insulin-stimulated glucose utilization and cholesterol metabolism. Therefore this tissue plays a notable role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, muscle has a significant role in the progression of dyslipidemia, diabetes and obesity. Surprisingly, the function of the NR4A subgroup in skeletal muscle metabolism has not been examined. Nevertheless, given the data on NR4A mediated gene regulation, and the potential therapeutic utility for the treatment of metabolic disease, the contribution of skeletal muscle to NR4A action must be defined. Correspondingly, the objective of this proposal is to examine the role of the NR4A subgroup and is relevant to understanding the basis of dyslipidemia and obesity.Read moreRead less
Integrating Health Technology Assessment And Service Delivery And Organisation To Maximise Health Gains
Funder
National Health and Medical Research Council
Funding Amount
$258,538.00
Summary
The public heath care system in Australia faces ever greater issues around demand (e.g. aging population) and supply (e.g. expensive new interventions). It is becoming ever more important to ensure that the money we spend on health is used efficiently. This study is a unique application that aims to improve the efficiency of the health service by assessing how scarce services can be best organised to maximise health benefits.