The Regulation Of Apolipoprotein E Secretion By Human Macrophages
Funder
National Health and Medical Research Council
Funding Amount
$516,078.00
Summary
One of the major inflammatory cells in the body, the macrophage, is involved in a number of diseases, including coronary disease. ApoE is made and released by macrophages and appears to protect against the inflammation of coronary disease and may affect other conditions, including Alzheimer's disease. We have discovered pathways regulating the production and release of apoE by macrophages, and in this project will study these pathways in great detail. By controlling the production of this import ....One of the major inflammatory cells in the body, the macrophage, is involved in a number of diseases, including coronary disease. ApoE is made and released by macrophages and appears to protect against the inflammation of coronary disease and may affect other conditions, including Alzheimer's disease. We have discovered pathways regulating the production and release of apoE by macrophages, and in this project will study these pathways in great detail. By controlling the production of this important molecule we may reduce our risk of heart disease, and may be able to treat a range of inflammatory conditions which currently untreatable.Read moreRead less
Cellular Mechanisms And Physiological Roles Of GLUT12 Mediated Glucose Transport In Glucose Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$499,000.00
Summary
Diabetes affects almost one million Australians, although only 50% are aware they have the disease. Type 2 diabetes accounts for about 90% of diabetes and usually occurs after the age of 40. As a leading cause of death, adult blindness, lower limb amputation, kidney failure, stroke and heart attack, diabetes has huge economic and social consequences and has been designated an Australian National Health priority. A clinical feature of Type 2 diabetes is high blood glucose levels. This occurs beca ....Diabetes affects almost one million Australians, although only 50% are aware they have the disease. Type 2 diabetes accounts for about 90% of diabetes and usually occurs after the age of 40. As a leading cause of death, adult blindness, lower limb amputation, kidney failure, stroke and heart attack, diabetes has huge economic and social consequences and has been designated an Australian National Health priority. A clinical feature of Type 2 diabetes is high blood glucose levels. This occurs because insulin does not effectively stimulate the transfer of glucose from the blood into muscle and fat. The reasons for this are not fully understood. Insulin normally works to move glucose transporter (GLUT) proteins to the surface of muscle and fat cells. One GLUT that has been studied extensively in muscle and fat is GLUT4. GLUT4 moves to the cell surface in response to insulin and this response is one of the defects that is known to occur in Type 2 diabetes. Glucose then accumulates in the blood, leading to many of the complications of diabetes. We have discovered a novel glucose transporter, GLUT12, that is also present in muscle and fat. We have shown that GLUT12, like GLUT4, responds to insulin. GLUT12 could therefore be a critical backup for GLUT4. We have also found that GLUT12 responds to glucose itself, suggesting a unique role in controlling blood glucose levels. We will explore how GLUT12 acts in muscle and fat cells to find whether GLUT12 can act as a backup for GLUT4. We will also study GLUT12 in tissue from normal animals and in animals with features of Type 2 diabetes. To determine the role of GLUT12 in maintaining normal blood glucose levels, we will produce mice with an inactive GLUT12 gene. Our research could identify novel ways of increasing GLUT12 activity. The eventual goal will be to find a pharmaceutical compound that can improve glucose transport into muscle, reduce high blood glucose levels and thus the complications of Type 2 diabetes.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE130100117
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Allosteric fingerprinting of G protein-coupled receptor monomers and oligomers. Allosteric modulation describes interactions between distinct, but conformationally linked, binding sites. Research will develop enabling technology using the unique profile, or 'fingerprint', of allosteric modulation at interacting and non-interacting G protein-coupled receptors to probe for receptor complexes within healthy and diseased tissue.
Development and Characterization of Chemokine Receptor Mimics. The proposed research will provide important fundamental insights into the molecular events underlying inflammatory diseases and cancer metastasis. The innovative nature of the research and the significance of the results will enhance Australia's international research standing. Moreover, the insights gained from this work will contribute to the development of therapies that will ultimately enhance the quality of life for Australia ....Development and Characterization of Chemokine Receptor Mimics. The proposed research will provide important fundamental insights into the molecular events underlying inflammatory diseases and cancer metastasis. The innovative nature of the research and the significance of the results will enhance Australia's international research standing. Moreover, the insights gained from this work will contribute to the development of therapies that will ultimately enhance the quality of life for Australians.Read moreRead less
Structure and function of heterodimeric amino acid transporters. Recently a new family of amino acid transporters has been identified, the members of which are involved in the delivery of amino acids between cells and tissues. All members display a rather unusual structure in that they require two subunits to be functional. The main aim of this study is to investigate the interaction between large and small subunits. The study will give insight how membrane proteins form complexes in the membran ....Structure and function of heterodimeric amino acid transporters. Recently a new family of amino acid transporters has been identified, the members of which are involved in the delivery of amino acids between cells and tissues. All members display a rather unusual structure in that they require two subunits to be functional. The main aim of this study is to investigate the interaction between large and small subunits. The study will give insight how membrane proteins form complexes in the membrane and how these interactions affect the function of a complex membrane protein.Read moreRead less
The Regulation Of Gene Expression During Adipogenesis
Funder
National Health and Medical Research Council
Funding Amount
$549,446.00
Summary
The body stores energy acquired from ingested food as fat droplets within storage cells termed adipocytes. The amount of fat varies between individuals and may also vary during an individual's life. The variations reflect differences in physiology, diet, and behaviour and have been the focus of intense study. Excessive accumulation of fat is a serious health problem as it is associated with conditions such as heart disease and diabetes. This grant application primarily concerns using a new line ....The body stores energy acquired from ingested food as fat droplets within storage cells termed adipocytes. The amount of fat varies between individuals and may also vary during an individual's life. The variations reflect differences in physiology, diet, and behaviour and have been the focus of intense study. Excessive accumulation of fat is a serious health problem as it is associated with conditions such as heart disease and diabetes. This grant application primarily concerns using a new line of genetically modified mice that have reduced fat. These mice lack a key gene regulatory protein that is implicated in fat accummulation and adipocyte formation. It is expected that a knowledge of the genes regulating the formation and function of fat storage cells will contribute to new strategies for controlling fat formation and will help in the prevention of diseases such as diabetes and heart disease.Read moreRead less
Assessing the physiological roles of ubiquitination in regulating neuronal ion channels, receptors and transporters. Significant alterations in the activity neuronal transporters and receptors occur during tissue injury and regeneration as well as in many neurodegenerative disease states. Modulation of the pathways that control these transporters is an emerging therapeutic target, however, the molecular basis of these control mechanisms remain poorly understood. The outcome of this project will ....Assessing the physiological roles of ubiquitination in regulating neuronal ion channels, receptors and transporters. Significant alterations in the activity neuronal transporters and receptors occur during tissue injury and regeneration as well as in many neurodegenerative disease states. Modulation of the pathways that control these transporters is an emerging therapeutic target, however, the molecular basis of these control mechanisms remain poorly understood. The outcome of this project will be a thorough characterisation of a novel regulatory paradigm in neurons that is likely to be crucial for neuronal development and regeneration, and will potentially provide novel therapeutic targets for various neuronal diseases.Read moreRead less
G-protein coupled receptor-mediated calcium signalling in parasympathetic neurons. External chemical stimuli act on specific cell-surface receptors of neurons resulting in an increase in the intracellular calcium ion concentration which acts as a second messenger to alter neuronal excitability. There are, however, many receptors acting through a number of closely related proteins involving complex intracellular signalling pathways which remain poorly understood. This project uses molecular, elec ....G-protein coupled receptor-mediated calcium signalling in parasympathetic neurons. External chemical stimuli act on specific cell-surface receptors of neurons resulting in an increase in the intracellular calcium ion concentration which acts as a second messenger to alter neuronal excitability. There are, however, many receptors acting through a number of closely related proteins involving complex intracellular signalling pathways which remain poorly understood. This project uses molecular, electrical and fluorescence techniques to elucidate the molecular basis for these interactions by identifying the roles individual proteins play in integrating diverse extracellular stimuli and neuronal excitablility in the peripheral nervous system.Read moreRead less
Functional ubiquitination of neuronal voltage-gated sodium channels. Alterations in the electrical properties of excitable cells occur during tissue injury and regeneration as well as many disease states. Preventing or controlling these changes is a key strategic therapeutic aim. It is, however, only through a comprehensive understanding of the molecular mechanisms that regulate cellular excitability that we can identify these therapeutic targets. The major outcome of this project will be a thor ....Functional ubiquitination of neuronal voltage-gated sodium channels. Alterations in the electrical properties of excitable cells occur during tissue injury and regeneration as well as many disease states. Preventing or controlling these changes is a key strategic therapeutic aim. It is, however, only through a comprehensive understanding of the molecular mechanisms that regulate cellular excitability that we can identify these therapeutic targets. The major outcome of this project will be a thorough characterisation of a novel pathway that is potentially crucial in the development, homeostasis and regeneration of the nervous system. Disruption of normal function of this system may underlie the hyperexcitability observed in mannu neurodegenerative conditions.Read moreRead less