Structural Characterisation Of SNARE Protein Complexes Involved In Insulin-regulated Glucose Transport
Funder
National Health and Medical Research Council
Funding Amount
$320,803.00
Summary
Insulin-regulated glucose transportation is defective in type 2 diabetes, a disease that is a major health problem worldwide and in some cases can lead to death. The aim of this work is to investigate the molecular structure and function of proteins critical to the transportation and delivery of glucose to muscle and fat cells, which will lead to the validation of new therapeutic targets and the development of new treatments for diabetes.
Neuronal communication relies on the process of exocytosis by which neurons release a neurotransmitter. Exocytosis is critical for the simplest muscle movement to complex tasks such as learning and memory, and is altered in several neurodegenerative pathologies. We will investigate how the protein Munc18 controls exocytosis. This research will be important for understanding how neurons communicate in health and disease and will be relevant to other processes such as insulin release in diabetes.
Macrophages are important cells at the front-line of immunity where one of their main roles is to release anti-bacterial proteins. We will study the macrophage molecules, subcellular organelles and pathways that help to release these proteins to kill bacteria and fight infection. Our studies will identify new cellular targets for boosting immunity and treating inherited diseases with defective macrophage function.
Modulating Neuronal Secretion By The PI3-kinase Pathway
Funder
National Health and Medical Research Council
Funding Amount
$516,855.00
Summary
Neuronal communication relies on the process of exocytosis by which neurons release neurotransmitter. Exocytosis is critical for the simplest reflex movement to complex tasks such as learning and memory, and is altered in several neurodegenerative pathologies. We will investigate how certain lipids control exocytosis. This research is important for understanding how neurons communicate in health and disease and is relevant to other processes such as insulin release in diabetes.
Structural Studies On SNARE Proteins Involved In Insulin Action
Funder
National Health and Medical Research Council
Funding Amount
$308,263.00
Summary
Diabetes mellitus, a disease characterised by high blood glucose levels, is caused by a relative or absolute deficiency in the activity of insulin. The blood-glucose lowering action of insulin is a result of its ability to stimulate glucose uptake by fat and muscle cells. A major goal of Professor James' laboratory is to identify molecules that are involved in this insulin-regulated uptake of glucose. Professor James has identified and characterised the glucose transporter, GLUT4, a protein that ....Diabetes mellitus, a disease characterised by high blood glucose levels, is caused by a relative or absolute deficiency in the activity of insulin. The blood-glucose lowering action of insulin is a result of its ability to stimulate glucose uptake by fat and muscle cells. A major goal of Professor James' laboratory is to identify molecules that are involved in this insulin-regulated uptake of glucose. Professor James has identified and characterised the glucose transporter, GLUT4, a protein that is normally stored inside muscle and fat cells. In response to insulin stimulation, GLUT4 moves to the cell surface where it functions to transport glucose into the cell. Over the past 5 years Professor James laboratory has, in conjunction with other groups, discovered several key proteins that are involved in the insulin-regulated movement of GLUT4 within the cell. We plan to exploit the therapeutic potential of this biological system by obtaining high resolution three dimensional structures of these key proteins. The resulting structural information will allow us to develop compounds that modify the function of these key proteins. Such compounds could prove useful as novel therapeutic agents in the treatment of diabetes. The purpose of this proposal is to begin to implement this goal. By combining the knowledge and reagents coming out of the work on insulin-regulated glucose transport in Professor James' laboratory with the molecular and structural biology expertise in Dr Martin's, Dr Halliday's and Prof Craik's laboratories we are in a unique position to achieve this highly significant goal.Read moreRead less
Deciphering The Molecular Basis Of SM Regulation Of Exocytosis
Funder
National Health and Medical Research Council
Funding Amount
$515,564.00
Summary
Diabetes, obesity, heart disease and physical inactivity are major and escalating health problems within western societies. These problems are all linked to, or aggravate, the condition known as insulin resistance. Insulin resistance occurs when normal levels of insulin are insufficient to remove glucose from the blood. In the normal situation, insulin regulates glucose uptake into muscle and fat cells by stimulating the movement of a glucose transport protein from inside the cell to the cell su ....Diabetes, obesity, heart disease and physical inactivity are major and escalating health problems within western societies. These problems are all linked to, or aggravate, the condition known as insulin resistance. Insulin resistance occurs when normal levels of insulin are insufficient to remove glucose from the blood. In the normal situation, insulin regulates glucose uptake into muscle and fat cells by stimulating the movement of a glucose transport protein from inside the cell to the cell surface. The trafficking of this protein is somehow disrupted in insulin resistance. The purpose of this research is to follow up our exciting preliminary results on this system to shed light on the molecular processes that regulate the trafficking of the glucose transporter. Information resulting from our studies will lead to a better understanding of insulin-stimulated glucose transport and may also unravel the details of a related cellular secretion system that regulates neurotransmission. Our hope is that by understanding at the molecular level how cells regulate secretion, we can in the future develop therapeutics to counteract many of today s major health problems.Read moreRead less
Obesity and diabetes are increasing in our community at an alarming rate. When one considers that Diabetes is a major cause of heart disease, stroke and kidney disease these diseases represent one of the most threatening for the future health of our nation. At the heart of these diseases is a disorder known as insulin resistance, or the inability of insulin to function correctly. The explosion in biological outcomes over the past decade has brought us closer than ever before to solving some of t ....Obesity and diabetes are increasing in our community at an alarming rate. When one considers that Diabetes is a major cause of heart disease, stroke and kidney disease these diseases represent one of the most threatening for the future health of our nation. At the heart of these diseases is a disorder known as insulin resistance, or the inability of insulin to function correctly. The explosion in biological outcomes over the past decade has brought us closer than ever before to solving some of the key questions associated with this problem. This proposal represents an exciting step forward in this area because our recent research combined with information from our international colleagues have led us to propose a new concept concerning the mechanism of insulin action. In this proposal we have formulated a series of molecular experiments to test this hypothesis which if correct will both change the way we think about this problem and provide new prospects for therapeutic design.Read moreRead less
Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tisse to respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in showing that insulin regulates glucose uptake into muscle ....Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tisse to respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in showing that insulin regulates glucose uptake into muscle and adipose tissue by stimulating the movement of a glucose transport protein from inside the cell to the cell surface. The purpose of this proposal is to dissect the molecular mechanisms by which this glucose transporter can be held inside the cell in the absence of insulin and then allowed to be released from this site moving to the surface in the presence of insulin. Our studies over the past 5 years have brought us much closer to understanding this process in detail. The identification of the molecules responsible for this regulatory step will not only aid our understanding of this process but it will also provide a valuable target for development of therapeutic agents that can be used to combat insulin resistance.Read moreRead less