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Understanding Sphingolipid Mediators Of Insulin Resistance
Funder
National Health and Medical Research Council
Funding Amount
$643,447.00
Summary
Sphingolipids are a class of lipid metabolites that have a variety of functions within cells. It has been known for some time that an accumulation of excess lipid, including certain sphingolipids, can adversely impact insulin action and glucose metabolism in cells. In this project we will a combination of strategies to test the hypothesis that the sphingolipid profile can be manipulated to have favourable effects on metabolism.
Do The Mitochondrial Sirtuin Enzymes, SIRT3 And SIRT5, Affect Insulin Action In Skeletal Muscle?
Funder
National Health and Medical Research Council
Funding Amount
$92,314.00
Summary
Metabolic disorders such as obesity, insulin resistance and type 2 diabetes are characterised by inappropriate handling of nutrients. Mitochondria are the primary site for nutrient oxidation in cells. Sirtuins such as SIRT3 and SIRT5 are abundant in mitochondria and may affect mitochondrial function and insulin action in skeletal muscle. Understanding the biochemical pathways involved in energy metabolism in skeletal muscle is crucial in the development of therapies for insulin resistance and ty ....Metabolic disorders such as obesity, insulin resistance and type 2 diabetes are characterised by inappropriate handling of nutrients. Mitochondria are the primary site for nutrient oxidation in cells. Sirtuins such as SIRT3 and SIRT5 are abundant in mitochondria and may affect mitochondrial function and insulin action in skeletal muscle. Understanding the biochemical pathways involved in energy metabolism in skeletal muscle is crucial in the development of therapies for insulin resistance and type 2 diabetes.Read moreRead less
Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tissue 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 tissue 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 (see http:--www.imb.uq.edu.au-groups-james-glut4 for an animated description of this process). 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
Mechanism Of Action Of Sec1p-like Proteins In Membrane Trafficking.
Funder
National Health and Medical Research Council
Funding Amount
$440,250.00
Summary
One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has ....One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has developed a complex assembly line of modifications that are added to proteins in a specific order as they travel to their final destination within the cell. This necessitates the accurate passage of molecules between compartments, a process known as vesicle transport. To orchestrate the complex network of vesicular transport steps between all of the various intracellular compartments it is necessary to employ complex machinery to guide and check that these steps occur with high fidelity. The goal of our research proposal is to define the function of one of the molecules involved in this control process, the so-called Sec1p proteins. The strength of our proposal lies in the diversity of our approach. We intend to explore the molecular advantages of a relatively simple eukaryotic organism, a yeast cell, and apply the findings obtained from this cell to a more complex but highly related vesicular transport process; that of the insulin-regulated movement of a glucose transporter in mammalian fat and muscle cells. While we intend to apply our findings to the treatment of patients with diabetes, it is our ultimate goal to be able to learn more about this fundamental cell biological process so that we can apply our knowledge to understanding many different disease states.Read moreRead less
Do Synaptic-like Mechanisms Control Insulin Secretion?
Funder
National Health and Medical Research Council
Funding Amount
$593,235.00
Summary
An estimated 415 million people world-wide were diagnosed with diabetes in 2015. One of the causal factors in disease is the dysregulation of insulin secretion. We have developed new techniques to study insulin secretion that has led us to propose a new model for secretory control. This proposal sets out experiments to critically test this model. The outcomes could have wide-reaching impact on understanding and for future treatment and prevention of the diabetes.
How Does Paternal Obesity Influence Offspring Glucose Tolerance?
Funder
National Health and Medical Research Council
Funding Amount
$503,398.00
Summary
Obesity and diabetes are closely related to these conditions in either parent, but how the father contributes is unclear. We have shown that normal females mated with obese fathers consuming high fat diet, produce offspring who develop glucose intolerance and impaired insulin secretion. This work will examine the mechanisms underlying this effect in the rat, testing a novel role for environmental factors in the father on disease in offspring that may be relevant to the growing obesity epidemic.
Prevention Of Multi-drug Resistant Tuberculosis In A High Prevalence Setting: ‘Connecting The DOTS’ In Vietnam
Funder
National Health and Medical Research Council
Funding Amount
$3,382,020.00
Summary
The close contacts of people with multi-drug resistant tuberculosis (MDR-TB) have a high risk of developing the disease. The V-QUIN MDR-TB Trial will evaluate the effectiveness of an oral antibiotic (levofloxacin) in preventing drug resistant TB among infected household contacts of TB patients. Household contacts from 10 Provinces in Vietnam will be randomly allocated to receive six-months of either levofloxacin or a placebo, and then followed for two years to see if they develop tuberculosis.
Multidrug Resistance Protein 1 Inhibitors To Sensitise Cancers To Chemotherapy
Funder
National Health and Medical Research Council
Funding Amount
$840,166.00
Summary
Multidrug resistance protein 1 (MRP1) is often present at high levels in cancer cells, where it pumps chemotherapy drugs back out, causing drug resistance. Inhibitors that block MRP1 would increase the effectiveness of chemotherapy. We have developed MRP1 inhibitors with promising activity in cancer cells and mouse tumours and will now develop these inhibitors for clinical application and commercialisation.
Modelling The Impact Of Strategies To Control Gonorrhoea And Minimise The Threat Of Antimicrobial Resistance In Remote Indigenous And Other High Risk Populations
Funder
National Health and Medical Research Council
Funding Amount
$467,079.00
Summary
Gonorrhoea is a serious public health issue in Australia. Notification rates are disproportionately high among Aboriginal and Torres Strait Islander people and men who have sex with men, and there is evidence of an emerging epidemic in the general heterosexual population. Additionally, available treatments are under threat from resistant strains. We will use mathematical modelling to evaluate strategies for controlling gonorrhoea and for minimising the threat of antimicrobial resistance.
The Structure And Function Of The Apical Domain In Insulin Secreting Beta Cells.
Funder
National Health and Medical Research Council
Funding Amount
$571,741.00
Summary
Loss of control of insulin secretion is causal in diabetes and therefore its understanding is a key goal to shed light on the disease. We have recently identified a new domain in the insulin secreting cells, called the apical domain. This proposal will define the role of this apical domain in controlling insulin secretion. The outcomes could provide new insights into how diabetes develops and new targets for therapies.