Pathogenesis of Alzheimer's disease: Dissecting synaptosomal dysfunction in transgenic animal models. There is no cure for Alzheimer's disease (AD). This project will dissect pathogenic mechanisms, identify new drug targets, and develop treatment strategies, all of which will be patented and eventually lead to a decrease in health costs in Australia. This research clearly falls under the national research priority of promoting and maintaining good health. Our findings are expected to benefit pat ....Pathogenesis of Alzheimer's disease: Dissecting synaptosomal dysfunction in transgenic animal models. There is no cure for Alzheimer's disease (AD). This project will dissect pathogenic mechanisms, identify new drug targets, and develop treatment strategies, all of which will be patented and eventually lead to a decrease in health costs in Australia. This research clearly falls under the national research priority of promoting and maintaining good health. Our findings are expected to benefit patients in addition to those suffering from AD, as pathocascades and pathogenic mechanisms are shared between a range of neurodegenerative disorders. Read moreRead less
Characterisation of a novel neural-specific ATPase in cholesterol transport. Ageing is determined by both genetic and metabolic factors. To a large part, the detailed mechanisms of ageing remain to be unexplored. Genetically, the timing of cell ageing entails the loss of telomeres (tips of chromosomes). However, the buildup of metabolic wastes resets the timing prematurely. Metabolic products accumulate from excess production or a shortfall of removal activity, which occurs in the various parts ....Characterisation of a novel neural-specific ATPase in cholesterol transport. Ageing is determined by both genetic and metabolic factors. To a large part, the detailed mechanisms of ageing remain to be unexplored. Genetically, the timing of cell ageing entails the loss of telomeres (tips of chromosomes). However, the buildup of metabolic wastes resets the timing prematurely. Metabolic products accumulate from excess production or a shortfall of removal activity, which occurs in the various parts of ageing cells in tissues such as brain. Traffic jams of cholesterol transport in the secretory pathway induce early ageing of the nerve cells. We investigate a novel mechanism controlling cholesterol transport in nerve cell ageing.Read moreRead less
Development of a gene delivery system to access neuronal cells. Understanding the pathways for gene delivery and efficient expression will result in new knowledge in the areas of biotechnology and cell biology. This project will result in significant new information on vesicular trafficking pathways in neurons. An effective gene delivery system will realise significant commercial potential for our partner organisations and economic benefit to other Australian industry. This project aligns direct ....Development of a gene delivery system to access neuronal cells. Understanding the pathways for gene delivery and efficient expression will result in new knowledge in the areas of biotechnology and cell biology. This project will result in significant new information on vesicular trafficking pathways in neurons. An effective gene delivery system will realise significant commercial potential for our partner organisations and economic benefit to other Australian industry. This project aligns directly with the National Research Priority of "Promoting and maintaining good health" with a specific benefit for patients that suffer mental and physical degeneration and for their families.Read moreRead less
Role of 3'-phosphorylated phosphoinositides in neurosecretion. Neurons communicate through the release of neurotransmitter by synaptic vesicles. Minute changes underlie normal processes such as memory and modifications of neurotransmitter level contribute to a number of neurological diseases. I am interested in deciphering the role of phosphoinositides, an inner membrane-based lipid, during steps leading to the fusion of a synaptic vesicle with the plasma membrane. I have recently discovered tha ....Role of 3'-phosphorylated phosphoinositides in neurosecretion. Neurons communicate through the release of neurotransmitter by synaptic vesicles. Minute changes underlie normal processes such as memory and modifications of neurotransmitter level contribute to a number of neurological diseases. I am interested in deciphering the role of phosphoinositides, an inner membrane-based lipid, during steps leading to the fusion of a synaptic vesicle with the plasma membrane. I have recently discovered that phosphatidylinositol-3 phosphate production was critical for the vesicle to acquire the competence to fuse with the plasma membrane. This project aim to understand by which mechanism this lipid interacts with the release machinery to promote such priming step.Read moreRead less
Novel modes of signalling of serotonin 5-HT2c receptors. This project focuses on a special family of receptor proteins that mediate the actions of the neurochemical, serotonin (5HT), in the human brain. These serotonin receptors are major targets for antidepressant and antipsychotic medications, and also play a role in anxiety, migraine and control of appetite. Despite the important role of serotonin receptors in health and disease, the mechanism of action of many drugs acting on these receptors ....Novel modes of signalling of serotonin 5-HT2c receptors. This project focuses on a special family of receptor proteins that mediate the actions of the neurochemical, serotonin (5HT), in the human brain. These serotonin receptors are major targets for antidepressant and antipsychotic medications, and also play a role in anxiety, migraine and control of appetite. Despite the important role of serotonin receptors in health and disease, the mechanism of action of many drugs acting on these receptors remains unknown. Our project will specifically investigate novel molecular mechanisms associated with serotonin receptor activity that may prove vital in understanding mechanisms of psychiatric illnesses, and how many psychiatric medicines actually work.Read moreRead less
Structural And Drug Discovery Studies Of Oxidative Stress Regulator, Thioredoxin-interacting Protein
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
Toxic oxygen molecules known as Reactive Oxygen Species (ROS) are by-product of normal metabolism. The excess of ROS is damaging and is well known to contribute to ageing process and age-related diseases such as cancer, diabetic complications, immune-system decline, and cardiovascular conditions to name a few. The human body possesses several defense systems that protect us from the excess of ROS maintaining a healthy level of ROS. A down-regulator of one of this systems, a protein called TXNIP, ....Toxic oxygen molecules known as Reactive Oxygen Species (ROS) are by-product of normal metabolism. The excess of ROS is damaging and is well known to contribute to ageing process and age-related diseases such as cancer, diabetic complications, immune-system decline, and cardiovascular conditions to name a few. The human body possesses several defense systems that protect us from the excess of ROS maintaining a healthy level of ROS. A down-regulator of one of this systems, a protein called TXNIP, has been recently discovered. The amount of TXNIP is increased in such conditions as high glucose, a first sign of diabetes, and under ischemia, a shortage of blood supply occurring during heart attack. This weakens the anti-oxidant defense systems and makes the organism more vulnerable to ROS exposure. Our team of researchers embarked on structural and functional studies of TXNIP with the purpose to identify small molecules that can interfere with the undesirable action of TXNIP. These molecules might become useful therapeutic agents to counteract weakening organism's ROS defense system caused by TXNIP in many disease conditions such as, cancer, diabetes and cardiac failure.Read moreRead less
Assembly Of Mitochondrial Respiratory Chain Complexes And Defects Associated With Disease
Funder
National Health and Medical Research Council
Funding Amount
$464,610.00
Summary
A group of protein assemblies termed respiratory complexes are found in the inner membrane of mitochondria in our cells and are responsible for producing most of our energy. These complexes consist of many different protein subunits and are built by the help of numerous known and unknown assembly factors. For example, assembly of Complex I of the respiratory chain requires 39 different proteins that are made outside mitochondria and are then transported inside to be somehow joined together with ....A group of protein assemblies termed respiratory complexes are found in the inner membrane of mitochondria in our cells and are responsible for producing most of our energy. These complexes consist of many different protein subunits and are built by the help of numerous known and unknown assembly factors. For example, assembly of Complex I of the respiratory chain requires 39 different proteins that are made outside mitochondria and are then transported inside to be somehow joined together with the 7 other subunits that are made by mitochondria. This is clearly a complicated procedure and we have little information on how its assembly is achieved. We do know however that mistakes in the assembly of these complexes (particularly Complex I) do happen. In Australia, about 50 children born each year have inherited disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others present later causing a range of degenerative diseases, particularly affecting brain, muscle and heart. Defects in the respiratory chain have also been implicated in Parkinson's disease, Alzheimer's disease, type-2 diabetes and in cell death. In order to understand how respiratory complex defects cause disease, we need to understand more about how these complexes are built. The aim of this proposal is to investigate how Complex I is assembled, how it interacts with other respiratory complexes, and to identify and characterise proteins that aid in its assembly. We will also analyse assembly defects in cells from patients with suspected respiratory complex deficiencies. This work will aid in our understanding of not only how protein complexes are built, but how defects in their assembly can cause disease. This will be informative to families of affected individuals and may aid in future diagnosis and prevention of diseases where defects in mitochondria are implicated.Read moreRead less
Regulation Of Pre-mRNA And MRNA Processing By The Neuron-specific Hu RNA-binding Proteins
Funder
National Health and Medical Research Council
Funding Amount
$477,750.00
Summary
The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, t ....The precise control of protein expression is absolutely critical in biology, and the key decisions about which genes are turned on or off at any one moment control the proper growth and maturation of an organism during development, and are responsible for the organism's homeostasis and proper response to environmental changes as an adult. Many gene expression programs are highly complex and controlled by regulating the activation of individual genes as they are copied from DNA to RNA. However, this activation is just the start of the process to produce an active protein. In higher organisms, these RNA copies almost always contain interruptions called introns, which must be excised from the RNA. Also, protein factors bound to specific RNAs can dictate whether the RNA is used to make protein or not, and these factors can also affect the localisation of the RNA to a specific sub-cellular destination, giving rise to highly localised protein expression. Evidence suggests that neurons are a cell type that rely heavily on mechanisms of RNA regulation. During development neurons become highly polarised, acquiring an axon which can elongate and find distant synaptic targets. While much is known about how axon growth cones respond to various guidance cues, the mechanisms by which the axon is able to translate this guidance cue information into structural changes which allow the growth cone to expand or collapse is largely unexplored. Recent evidence suggests that accurate growth cone guidance is absolutely dependent upon local protein synthesis. The functional corollary of this finding is that axon guidance requires RNA localisation and control of protein synthesis of RNAs in the growth cone. This phenomenon of spatial gene regulation within an individual cell is a central research interest for understanding how the brain functions.Read moreRead less
Proteolysis of binding protein complexes regulates bioavailability of insulin-like growth factor (IGF). We aim to determine how growth factors kept inactive in complexes in the blood can become free and active. The fundamental knowledge gained will help us understand the regulation of growth factors' availability to tissues and develop novel or more effective delivery systems for therapeutic growth factors that could impact on several conditions including diabetes, growth disorders and critical ....Proteolysis of binding protein complexes regulates bioavailability of insulin-like growth factor (IGF). We aim to determine how growth factors kept inactive in complexes in the blood can become free and active. The fundamental knowledge gained will help us understand the regulation of growth factors' availability to tissues and develop novel or more effective delivery systems for therapeutic growth factors that could impact on several conditions including diabetes, growth disorders and critical illness. This project therefore benefits Australia at two levels: by maintaining our international leadership in the study of these important growth-regulatory molecules, and by providing a better understanding of physiological mechanisms that might benefit the health of Australians and provide opportunities to develop novel therapeutics.Read moreRead less