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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100089
Funder
Australian Research Council
Funding Amount
$700,000.00
Summary
Super-resolution fluorescence microscopy. The prestigious journal Nature Methods named super-resolution fluorescent microscopy as the Method of the Year 2008. This recognition is justified because fluorescent imaging on the molecular scale will revolutionise biological sciences. It will literally change the way we see the smallest building blocks of life and this allows researchers to identify the function of proteins and lipids in health and disease. This breakthrough technology is currently no ....Super-resolution fluorescence microscopy. The prestigious journal Nature Methods named super-resolution fluorescent microscopy as the Method of the Year 2008. This recognition is justified because fluorescent imaging on the molecular scale will revolutionise biological sciences. It will literally change the way we see the smallest building blocks of life and this allows researchers to identify the function of proteins and lipids in health and disease. This breakthrough technology is currently not available to researchers in Australia. Super-resolution fluorescence microscopy would extend Australia's leading position in the fundamental biological sciences, bio- and nano-technologies as well as imaging and microscopy.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
Discovery Early Career Researcher Award - Grant ID: DE140101626
Funder
Australian Research Council
Funding Amount
$394,179.00
Summary
Flotillin link membrane microdomains to signalling endosome during T cell activation. This project aims to determine the mechanisms that connect signalling microdomains at the cell surface to intracellular signalling endosomes to regulate T cell activation. A T cell immune response begins with the reorganisation of the plasma membrane to yield two-dimensional signalling microdomains that must be connected to the three-dimensional microarchitecture of the endocytic matrix for full T cell activati ....Flotillin link membrane microdomains to signalling endosome during T cell activation. This project aims to determine the mechanisms that connect signalling microdomains at the cell surface to intracellular signalling endosomes to regulate T cell activation. A T cell immune response begins with the reorganisation of the plasma membrane to yield two-dimensional signalling microdomains that must be connected to the three-dimensional microarchitecture of the endocytic matrix for full T cell activation. This project hypothesises that Flotillin form distinct signalling microdomains in the plasma membrane that internalise to constitute an independent endocytic pathway. Using single-molecule and ultra-fast fluorescence imaging, the project will demonstrate that Flotillin represent a unique two-dimensional to three-dimensional regulatory mechanism for T cell signalling.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100224
Funder
Australian Research Council
Funding Amount
$250,000.00
Summary
Multi-mode fluorescence microscope for visualising the dynamics of cellular processes at the single-molecule level. Fluorescence is the emission of light by a substance that has absorbed light of a different wavelength. This fluorescence microscopy facility will allow the visualisation of the dynamic processes that define life at the molecular level. This insight will help us understand cellular function and how it is impaired in various diseases including cancer and neurodegenerative disorders ....Multi-mode fluorescence microscope for visualising the dynamics of cellular processes at the single-molecule level. Fluorescence is the emission of light by a substance that has absorbed light of a different wavelength. This fluorescence microscopy facility will allow the visualisation of the dynamic processes that define life at the molecular level. This insight will help us understand cellular function and how it is impaired in various diseases including cancer and neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease.Read moreRead less
The Molecular Mechanism Of Ion-coupled Transport In The Brain
Funder
National Health and Medical Research Council
Funding Amount
$441,407.00
Summary
Cells in the brain communicate through chemical signals called neurotransmitters. Neurotransmitter transporters reside in the membranes of cells and are responsible for regulating levels of these chemicals in the brain. They play an important role in the normal function of the human brain but their dysfunction is responsible for many diseases including Alzheimer's disease and motor neuron disease. It is crucial to understand how these proteins work in both normal and disease states.
Assembly and stability of human voltage-gated potassium channels. The Kv11.1 voltage-gated potassium channel is an important regulator of cardiac function and a problem for the pharmaceutical industry due to its promiscuity with respect to drug binding. This project aims to investigate how Kv11.1 channels fold and assemble into tetramers and what stabilizes them in the cell membrane. Borrowing from insights gained from the structural analysis of G-Protein coupled receptors, the project intends t ....Assembly and stability of human voltage-gated potassium channels. The Kv11.1 voltage-gated potassium channel is an important regulator of cardiac function and a problem for the pharmaceutical industry due to its promiscuity with respect to drug binding. This project aims to investigate how Kv11.1 channels fold and assemble into tetramers and what stabilizes them in the cell membrane. Borrowing from insights gained from the structural analysis of G-Protein coupled receptors, the project intends to apply a novel protein stabilization strategy to facilitate the structural analysis of Kv11.1 channels. The successful completion of the project could reveal important insights into how these molecular machines work as well as enable atomic level studies of how drugs interact and bind to these channels.Read moreRead less
Defining systems that clear dangerous misfolded proteins from body fluids. The project intends to establish how the human body defends itself against protein-folding related disease and loss of quality of life. Exposure to everyday physical and chemical stresses can cause proteins to lose their normal shape and become misfolded. Misfolded proteins are causally involved in human ageing and serious diseases (for example, Alzheimer's disease). However, the body does have a protective system that cl ....Defining systems that clear dangerous misfolded proteins from body fluids. The project intends to establish how the human body defends itself against protein-folding related disease and loss of quality of life. Exposure to everyday physical and chemical stresses can cause proteins to lose their normal shape and become misfolded. Misfolded proteins are causally involved in human ageing and serious diseases (for example, Alzheimer's disease). However, the body does have a protective system that clears dangerous misfolded proteins from body fluids. Using cutting-edge approaches and a novel animal model, the project aims to establish how this system works. The outcomes are expected to improve understanding of the molecular processes affecting human ageing and disease and strengthen the framework needed to develop better strategies to combat these.Read moreRead less
Deadly Commute - Targeting The Trafficking Mechanisms That Licence Inflammatory Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$774,544.00
Summary
MLKL is a protein naturally found inside cells. MLKL is activated by inflammation. Once activated, MLKL relocates to the outer periphery of cells and kills them. Gut cells are especially vulnerable to death-by-MLKL and this problem causes Inflammatory Bowel Disease. Using cutting edge microscopy, we have discovered how MLKL moves to the periphery of cells prior to killing them. We will test if blocking this movement of MLKL to the cell periphery stops gut death and Inflammatory Bowel Disease.