Regulation Of Endosome Function By The AAA-ATPase Vps4
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
Cells respond to many signals from the environment. Some signals tell cells to grow and divide and other signals tell cells to rest. These signals are usually in balance in healthy cells. To prevent cells from growing and dividing in an uncontrolled manner and forming a cancer, there are mechanisms to turn off signals for growth. One mechanism is to destroy the proteins responsible for growth signalling. This involves flipping (by a process called multivesicular body, or MVB, sorting) the signal ....Cells respond to many signals from the environment. Some signals tell cells to grow and divide and other signals tell cells to rest. These signals are usually in balance in healthy cells. To prevent cells from growing and dividing in an uncontrolled manner and forming a cancer, there are mechanisms to turn off signals for growth. One mechanism is to destroy the proteins responsible for growth signalling. This involves flipping (by a process called multivesicular body, or MVB, sorting) the signalling protein from one side of the membrane where signalling occurs to the other side where signalling cannot occur and where the signalling protein can be degraded. Interestingly, it has recently been discovered that some viruses (including the AIDS virus) use the same MVB sorting mechanisms to escape from infected cells. Instead of undergoing MVB sorting into an internal compartment and getting degraded, however, the virus is able to use the same mechanism to flip out of the cell. How MVB sorting occurs is not known, but the mechanism has been conserved through evolution and even microbes like yeast can perform MVB sorting of proteins. We are investigating a component of the MVB sorting mechanism known as Vps4 which is present in both human cells and in yeast cells. Since the human Vps4 and yeast Vps4 seem to function in the same way, and since powerful molecular genetic approaches can be used in yeast to elucidate how proteins function (some of which are not possible with human cells), we are using yeast to investigate Vps4 function. Once we understand how the yeast Vps4 works, we will be able to test if human Vps4 works the same way. Understanding the MVB sorting mechanism will give us information on how cells prevent uncontrolled growth and division and may also help us find ways of preventing AIDS infection.Read moreRead less
Molecular Analysis Of The Function Of A Muscle-specific Caveolar Protein
Funder
National Health and Medical Research Council
Funding Amount
$462,528.00
Summary
Muscular dystrophy is one of the most common and most debilitating inherited diseases in humans. Muscle from patients with muscular dystrophy is highly susceptible to damage leading to muscle wasting. In order to understand muscular dystrophy and to design therapeutic treatments, it is essential that researchers gain a detailed understanding of the workings of the muscle cell surface membrane. Caveolae are small pits which cover the entire surface of the muscle fibre. The major protein of muscle ....Muscular dystrophy is one of the most common and most debilitating inherited diseases in humans. Muscle from patients with muscular dystrophy is highly susceptible to damage leading to muscle wasting. In order to understand muscular dystrophy and to design therapeutic treatments, it is essential that researchers gain a detailed understanding of the workings of the muscle cell surface membrane. Caveolae are small pits which cover the entire surface of the muscle fibre. The major protein of muscle caveolae is caveolin-3, and mutations in this protein cause some forms of muscular dystrophy. This proposal aims to examine the function of this protein using a number of strategies. The caveolin-3 gene will be disrupted in mice to produce mice which lack this protein. The muscle from these mice will then be examined to see what effect the lack of this protein has on muscle function and whether this muscle is similar to that in patients with muscular dystrophy. The muscle from these mice will then be used to design treatments for the disease. In addition, we will search for proteins which work together with caveolin-3 in order to understand how the protein works in healthy and diseased muscle.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
Road Traffic Injury Prevention: A Public Health Approach
Funder
National Health and Medical Research Council
Funding Amount
$380,558.00
Summary
The proposed research program will have a positive impact on road safety in Australia, particularly for young drivers, by using a series of intervention and observational studies to provide strong evidence for policy makers, and build research capacity. Furthermore, the development and adaptation of effective road safety interventions for low income countries in the region has the potential to improve health and economic conditions for many people in these countries.