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.
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.
The Preferential Release Of Young Insulin Secretory Granules.
Funder
National Health and Medical Research Council
Funding Amount
$670,005.00
Summary
The aim of this study is to investigate the cause of reduced glucose induced insulin secretion in type 2 diabetes. In pancreatic beta-cells, insulin is packaged and stored in secretory granules (SGs). Upon stimulation, these SGs deliver insulin to the bloodstream. It is known that insulin SGs exist in two functionally distinct pools; and one pool is preferentially secreted upon stimulation. How a cell can differentiate the two SG pools is unclear, and we will address this issue in this project.
Mechanism Of Action Of Sec1p-like Proteins In Membrane Trafficking
Funder
National Health and Medical Research Council
Funding Amount
$234,936.00
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
Effect Of Sex Steroids, Inflammation, Environmental And Biopsychosocial Factors On Cardiometabolic Disease Risk In Men
Funder
National Health and Medical Research Council
Funding Amount
$1,817,271.00
Summary
Heart disease is more frequent and occurs at an earlier age in men than women. The reason is unknown. Apart from obesity and associated disturbances of metabolism, changes in sex hormones such as testosterone, together with the effects of inflammation may be important, and may in turn be affected by environment, lifestyle behaviours, and stress. To untangle these relationships, we will use cutting edge technology, in a large sample of men, in partnership with other international scientists.
Regulation Of Secretion Of The Fungal Virulence Determinant, Phospholipase B
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Serious systemic infections due to fungi have increased dramatically in the past few years, especially in people with poorly functioning immune systems. Treatment of these conditions is problematic because the few drugs which are available are not highly effective, and-or cause significant side-effects. Little is understood of how fungi cause disease, and this problem must be addressed if these infections are to be contained. We have discovered that the enzyme, phospholipase B (PLB), is secreted ....Serious systemic infections due to fungi have increased dramatically in the past few years, especially in people with poorly functioning immune systems. Treatment of these conditions is problematic because the few drugs which are available are not highly effective, and-or cause significant side-effects. Little is understood of how fungi cause disease, and this problem must be addressed if these infections are to be contained. We have discovered that the enzyme, phospholipase B (PLB), is secreted by the disease-causing fungus, Cryptococcus neoformans, and that it is important in enabling the fungus to invade the host's cells and spread around the body from the lungs to the brain, where it can cause meningoencephalitis. PLB is also produced by other disease-causing fungi. The mechanism of PLB secretion is completely unknown. In this project we aim to determine the pathways involved in PLB secretion with the intention of exploiting steps unique to pathogenic fungi, for the future design of new anti-fungal drugs.Read moreRead less
De Novo Mutations And The Pathogenesis Of Childhood-onset Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,406,510.00
Summary
This project aims to reveal the gene abnormalities that cause devastating autoimmune diseases to develop in some children, such as Type 1 diabetes, juvenile arthritis and autoimmune destruction of blood cells. The project will use new technologies to identify alterations in the DNA sequence of a child compared to either of their parents, and to test suspicious DNA alterations in laboratory mice in order to understand the gene effects and evaluate new treatments.
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
ManagemenT Of ChronIc CardioMetabolic DiseasE And Treatment DiScontinuity In Adult ADHD PAtieNts (TIMESPAN)
Funder
National Health and Medical Research Council
Funding Amount
$499,613.00
Summary
The aim of TIMESPAN is to improve the management of patients with Attention Deficit Hyperactivity Disorders (ADHD) and co-occurring cardiometabolic disease (i.e. obesity, type-2 diabetes, and cardiovascular disease). Inadequate treatment of these common conditions can lead to premature death and substantial societal costs. We will use linked electronic health records and novel research methods to improve clinical outcomes and quality of life of adults with ADHD and cardiometabolic disease.