Novel Microtubule Association Sequences From Rabies Virus; Subversion Of Antiviral Responses And Use In Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$529,632.00
Summary
The P-protein from rabies virus (RV) has distinct sequences that enable it to exploit the cellular skeleton (cytoskeleton) to localise efficiently in the host cell nucleus to exert pathogenic effects, or to perturb the cytoskeleton and thereby impair the host cell anti-viral response and immune response generally. We aim to characterise these properties in detail, demonstrate their importance to RV pathogenicity, and test the utility of the P-protein sequences in drug delivery.
Investigating A Novel Generic Approach To Anti-Infective Agents
Funder
National Health and Medical Research Council
Funding Amount
$636,833.00
Summary
Alpha helical regions of proteins mediate infection by viruses and bacteria. Short peptides corresponding to these helical segments are unstructured in water. We will (a) test new technology for its generic capacity to stabilize 1-4 turns of alpha helical viral and bacterial peptides, (b) test small molecules for helical structure, and (c) test for antiviral, antibacterial or immunogenicity activity in cell assays. Proof of the technology may benefit many fields of medicine and health prevention ....Alpha helical regions of proteins mediate infection by viruses and bacteria. Short peptides corresponding to these helical segments are unstructured in water. We will (a) test new technology for its generic capacity to stabilize 1-4 turns of alpha helical viral and bacterial peptides, (b) test small molecules for helical structure, and (c) test for antiviral, antibacterial or immunogenicity activity in cell assays. Proof of the technology may benefit many fields of medicine and health prevention.Read moreRead less
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
Viral disease is a major health hazard in the modern world. SV40 is a relatively simple virus which must enter mammalian cells in order to replicate. As it does so, it causes the infected cell to divide and hence triggers tumour formation in the host. This proposal is aimed at understanding how SV40 enters cells, and then passes to the nucleus where it replicates. Most viruses have hijacked existing pathways into cells. For example, some viruses have used the pathway by which cells take up nutri ....Viral disease is a major health hazard in the modern world. SV40 is a relatively simple virus which must enter mammalian cells in order to replicate. As it does so, it causes the infected cell to divide and hence triggers tumour formation in the host. This proposal is aimed at understanding how SV40 enters cells, and then passes to the nucleus where it replicates. Most viruses have hijacked existing pathways into cells. For example, some viruses have used the pathway by which cells take up nutrients from the external medium. However, we have shown that SV40 uses a completely novel pathway involving surface pits called caveolae. The subsequent steps in the pathway are unknown and have been difficult to study. We have discovered a number of agents which inhibit infection by SV40. In this proposal we will characterise the infectious entry pathway by investigating exactly where in the cell these agents work. We will then isolate the virus from within the cell and attempt to reconstitute part of the viral entry pathway in vitro. These studies will provide insights into the entry pathway of the virus which may lead to new therapeutic strategies to combat viral disease. In addition, study of this pathway, leading from the cell surface to the nucleus, may provide new avenues for drug delivery and-or gene targetting.Read moreRead less