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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
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
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
Cellular and molecular mechanisms for gut homeostasis in mammals. Certain molecules are responsible for gut homeostasis. This project aims to develop new tools to manipulate the cellular and molecular pathways around these molecules, which should provide benefit for human and animal health. This project will test whether the basis of many health conditions is disrupted gut homeostasis, through changes in diet and our gut bacteria.
The biogenesis of bacterial outer membranes: how bacteria build their surface coating. This project will determine how bacteria build their outer membranes. The outer membrane protects 'probiotic bacteria' in the human intestine and enables 'pathogenic' bacteria to cause infectious diseases. The project presents outstanding training opportunities with the use of cutting edge technology and the development of skills not common in Australia.
A novel click chemistry approach to identify learning and memory molecules. This project seeks to contribute to a deeper understanding at a molecular level of how memory is stored in neurons. Long-term memories do not form immediately after learning. Initially fragile, they become resistant to disruption through a process known as memory consolidation. In a second process, termed reconsolidation, pre-established memories are updated and re-stored. Both processes depend on protein synthesis, but ....A novel click chemistry approach to identify learning and memory molecules. This project seeks to contribute to a deeper understanding at a molecular level of how memory is stored in neurons. Long-term memories do not form immediately after learning. Initially fragile, they become resistant to disruption through a process known as memory consolidation. In a second process, termed reconsolidation, pre-established memories are updated and re-stored. Both processes depend on protein synthesis, but little is known about the particular sets of proteins that are involved. The project plans to apply a novel biochemical protocol to a newly established transgenic mouse model that allows the visualisation and identification of newly synthesised proteins in the hippocampus, a brain area that is critical in memory formation.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
Unlocking malaria invasion by ultraresolution microscopy. This project describes the microscopic analysis of malaria-causing parasites invading human blood cells. The project aims to better understand how this invasion works and to understand how it might be inhibited.
Iron accumulation in the nematode C.elegans: a model of ageing. This project will investigate the role of biological metals in the process of ageing, the causes of which remain unresolved. The practical outcomes for society are broad; beyond improving understandings of the basic biology of ageing, this study will provide new insight and approaches that can be used to optimise lifespan.