Liver damage after liver surgery or shock is called ischemia-reperfusion injury (IRI). Recovery after surgical removal of liver tissue is due to liver regeneration. IRI and liver regeneration are controlled by specialised proteins called cytokines, one of which, TRAIL, is essential for both IRI and liver regeneration. This research is to find out how TRAIL exerts such seemingly opposite effects. The aim is to learn how to protect the liver against damage, and to stimulate its recovery.
Pathophysiological Significance Of Reverse Signaling Through Membrane TNF
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surfac ....Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surface of the cell and then it is 'clipped off' and released as a smaller, soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We believe that binding of tumour necrosis factor receptors to the cytokine while it is in its membrane form can also send a message backwards, into the cell bearing the tumour necrosis factor. This process, known as reverse signalling, then changes the activity of this cell. In this project we will investigate this phenomenon in detail. The results will be extremely relevant to new methods of treatment of diseases, that rely either on 'masking' tumour necrosis factor by administering soluble forms of its receptor or on blocking the release of the soluble form of the molecule from the surface of the cell. Our work will enable us to understand the consequences of these approaches more fully. We will also be looking at the role of the membrane form of tumour necrosis factor in a model of infectious disease. Influenza virus is responsible for a great deal of morbidity and mortality around the world. We, and others, have shown, in a mouse model, that some cells in the lungs make tumour necrosis factor during the course of viral pneumonia. Here we will determine whether the membrane form of this cytokine plays a role in clearing virus or causing some of the complications of this disease. This also may have relevance to other inflammatory and infectious disease.Read moreRead less
Analysis Of CD95L And TRAIL Apoptotic Pathways In Glioma.
Funder
National Health and Medical Research Council
Funding Amount
$423,055.00
Summary
Most patients with the brain cancer malignant glioma die within two years of diagnosis, thus innovative approaches to treatment are desperately needed. Mutations which prevent the precancerous cells from responding to suicide (apoptotic) signals can contribute to tumourigenesis. As standard treatment regimes act by inducing this cellular suicide machinery, tumour cells with apoptotic pathway alterations can be resistant to conventional therapies. Malignant gliomas are typically resistant to chem ....Most patients with the brain cancer malignant glioma die within two years of diagnosis, thus innovative approaches to treatment are desperately needed. Mutations which prevent the precancerous cells from responding to suicide (apoptotic) signals can contribute to tumourigenesis. As standard treatment regimes act by inducing this cellular suicide machinery, tumour cells with apoptotic pathway alterations can be resistant to conventional therapies. Malignant gliomas are typically resistant to chemo- and radiotherapy, and therefore may have altered apoptotic pathways. By identifying the components of apoptotic pathways in glioma cells, rational design of either novel drugs, or treatments which will restore-enable susceptibility of the tumour cells to currently available therapies will be feasible. Here we will focus on the suicide pathways triggered by the molecules CD95L and TRAIL. We will characterise the sensitivity of glioma cells to CD95L and TRAIL, chemotherapeutic drugs and irradiation. We will then systematically survey the molecules implicated in CD95L and TRAIL-mediated cell death, based on studies in other cell types, to determine the relevant components of the molecular pathways which lead to apoptosis following CD95L-TRAIL exposure. We will also assess the roles played by known inhibitors, in determining resistance to CD95L and-or TRAIL, and will perform screens for novel inhibitors of these pathways. This study will elucidate the molecules responsible for the CD95L-TRAIL-mediated apoptosis seen in some glioma cells, and the molecules which confer resistance to these treatments in others. We will also learn whether the typical resistance to chemo- and radiotherapy observed in gliomas is mechanistically linked to resistance to CD95 and-or TRAIL resistance. This knowledge will be valuable for the rational design of diagnostic and therapeutic agents for glioma, and potentially for other diseases.Read moreRead less