Macrophages are white blood cells that provide front line defence against infection by initiating inflammatory responses by ingesting or phagocytosing microbes and by releasing soluble messengers (cytokines) to recruit other immune cells. These defensive functions require extensive trafficking of proteins within the macrophages. Protein trafficking is orchestrated in part by a family of membrane fusion proteins called SNAREs. By defining the relevant SNAREs, we have recently discovered a much ac ....Macrophages are white blood cells that provide front line defence against infection by initiating inflammatory responses by ingesting or phagocytosing microbes and by releasing soluble messengers (cytokines) to recruit other immune cells. These defensive functions require extensive trafficking of proteins within the macrophages. Protein trafficking is orchestrated in part by a family of membrane fusion proteins called SNAREs. By defining the relevant SNAREs, we have recently discovered a much acclaimed and novel pathway that allows efficient, combined cytokine secretion and phagocytosis in macrophages. Our studies proposed here will now expand on this discovery by comparing the phagocytic process, in terms of SNARE-mediated membrane and cytokine trafficking, for a wide range of microbes, highlighting differences that could provide new avenues for drug development. Moreover, since our strategy of using SNAREs to investigate and map trafficking pathways has proven so successful, we will now launch a major large-scale initiative to study ALL SNARE-mediated trafficking pathways in macrophages using a discovery pipeline of assays, including live cell imaging, we have developed. This will provide valuable information on many SNAREs including those associated with disease, and will elucidate trafficking pathways governing all macrophage actions in immunity, including cytokine secretion and antigen presentation. All of these pathways are highly relevant to current drug targets being used clinically or studied in inflammatory disease and for the development of vaccines.Read moreRead less
Regulating The Secretion Of Inflammatory Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$558,441.00
Summary
Cytokines or chemical messengers released by cells are essential for controlling immune responses but, in excess, they cause Crohn's disease and arthritis. Our research aims to block cytokine release as a novel way to ameliorate disease. We have identified specific cellular proteins, called golgins, that can be targeted to reduce cytokines. Here, characterization of golgin mediated cytokine transport in cells and in a mouse disease model is necessary to translate these findings for human benefit
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
$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