Caspase 8 Apoptotic Signalling Induced By The Inflammasome
Funder
National Health and Medical Research Council
Funding Amount
$603,126.00
Summary
The death of cells of our body can be an active and purposeful process. Programmed death occurs in response to infection or as a defence against cancerous changes. If a virally infected cell can die prior to replication of the virus, this will control the infection. We have investigated cell death in response to DNA found in the cytoplasm of cells, which can be an indication of infection. The novel cell death pathway we are characterising is relevant to defence against infection and tumours.
Autophagy And Growth Signalling In Developmentally Programmed Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$594,133.00
Summary
Cell death is essential for normal development and deregulated cell death results in many diseases. We have recently discovered a potentially novel mechanism of developmental cell death that involves autophagy (a type of self-degradation). Our studies will now examine the mechanism of autophagic cell death and study how cell growth regulation is integrated in this pathway. This will provide us important knowledge into the complex role of autophagy in cancer.
Cell death is a normal process that permits the growth and defense of our vital tissues. One kind of cell death, necroptosis, is characterised by the swelling and bursting of cells, triggering inflammation. Necroptosis is a key feature of illnesses ranging from colitis to arthritis, and contributes to the brain and heart damage that follows strokes and heart attacks. Understanding necroptotic cell death will pave the way for new therapies for those who suffer from these devastating conditions.
Understanding How BH3-only Proteins Initiate Apoptosis In Response To Chemotherapy
Funder
National Health and Medical Research Council
Funding Amount
$481,124.00
Summary
Failure to initiate cell death is a hallmark in the development of the majority of cancers and killing all tumour cells is essential for effective cancer treatment. A group of proteins termed the BH3-only proteins normally sense cell stress to trigger cell death. Their dysregulation contributes to cancer and failure to respond to chemotherapy. Understanding how these proteins function to induce cell death will allow the design of drugs that mimic this activity for improved cancer therapy.
Understanding The Biological Regulation Of MLKL And Its Role In Necroptotic Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$656,979.00
Summary
Cell death is a normal process that permits the growth and defence of our vital tissues. One kind of cell death, necroptosis, is characterized by the swelling and bursting of cells. When cells ‘explode’ in this uncontrolled way they provoke an inflammatory response. This may be a factor behind illnesses ranging from colitis to cardiovascular disease. Understanding necroptotic cell death may pave the way for new therapies for those that suffer from these devastating conditions.
Cell death by a specialised process known apoptosis is a way of deleting unwanted and harmful cells from the body. As such, aberrant apoptosis is associated with a wide array of diseases including cancer. For example, abnormal levels of proteins that suppress apoptosis or enhance cell survival can result in cancer and often produce resistance to chemotherapy. To understand and treat cancers that result from aberrant apoptosis we need to know at a molecular level how apoptosis is regulated. Centr ....Cell death by a specialised process known apoptosis is a way of deleting unwanted and harmful cells from the body. As such, aberrant apoptosis is associated with a wide array of diseases including cancer. For example, abnormal levels of proteins that suppress apoptosis or enhance cell survival can result in cancer and often produce resistance to chemotherapy. To understand and treat cancers that result from aberrant apoptosis we need to know at a molecular level how apoptosis is regulated. Central to the apoptosis execution are a group of enzymes called caspases that target many cellular proteins for specific cleavage. In this proposal, we will investigate the function of one of the caspases (called caspase-2), in order to better understand its potential role in the apoptosis of cancer cells. A number of recent reports suggest that caspase-2 levels are reduced in many cancer cells. The human caspase-2 gene localizes to a chromosomal region frequently affected- deleted in leukaemia, and caspase-2 levels have been proposed to be predictors of remission and survival in patients with some types of leukaemia. We will study if loss of caspase-2 in cancer cells makes them resistant to killing by drugs and if mice lacking caspase-2 have an increased potential to develop cancer. Understanding caspase-2 function and its regulation is likely to provide new therapeutic opportunities and potential targets for cancer therapy.Read moreRead less
Evolutionary Conservation Of Caspase Regulatory Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$585,215.00
Summary
Apoptosis is a highly controlled process by which metazoans eliminate unwanted and dangerous cells. Dysregulation of apoptosis can contribute to many conditions including cancer, autoimmune and degenerative diseases. To develop therapeutic reagents that promote cell death when it fails to occur, or prevent it from happening inappropriately, it is necessary to understand the mechanisms controlling apoptosis. To date, many of the important insights into mammalian cell death signalling have been in ....Apoptosis is a highly controlled process by which metazoans eliminate unwanted and dangerous cells. Dysregulation of apoptosis can contribute to many conditions including cancer, autoimmune and degenerative diseases. To develop therapeutic reagents that promote cell death when it fails to occur, or prevent it from happening inappropriately, it is necessary to understand the mechanisms controlling apoptosis. To date, many of the important insights into mammalian cell death signalling have been informed by studies of apoptotic pathways in simpler, experimentally tractable model organisms. This project will exploit biochemical approaches and powerful yeast-based tools developed by CI-A to further explore cell death pathways of the nematode Caenorhabditis elegans, and compare these with mammalian apoptosis pathways. Key findings will be verified using genetic approaches. Most apoptotic stimuli ultimately kill mammalian, insect or nematode cells by triggering activation of proteases termed caspases. However, the mechanisms by which caspase activity is regulated appear to differ somewhat between mammals and worms. We will address two general possibilities: either these animals really do differ significantly in the upstream regulation of cell death pathways, or that functional counterparts of key components have not hitherto been identified or fully characterised. Understanding the way in which mammalian apoptosis is regulated will aid in the design of diagnostic and therapeutic reagents for the many diseases in which dysregulation of apoptosis has been implicated. This project seeks to define the extent to which apoptotic regulation is conserved between mammals and nematodes. This knowledge will enable researchers to maximise the utility of nematode cell death models for the further elucidation of mammalian cell death regulatory mechanisms, and to explore how apoptosis can be manipulated for clinical benefit.Read moreRead less
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and, in general, to maintain the correct number of cells in the body. As such, misregulation of apoptosis is associated with the pathogenesis of a wide array of diseases. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases called caspases, that target many cellular proteins for specific cleavage. The activation of caspases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. If we understand how these regulatory mechanisms operate, we can then formulate strategies that are targeted towards pathologies involving abnormal apoptosis. In this proposal we will use vinegar fly as a model to study the function of caspases in development. We believe that results from this proposal will have several major benefits. Firstly, they will provide important insight into the mechanisms of developmental apoptosis thereby filling many gaps in our current knowledge. Secondly, the study will endeavour to identify new molecules-pathways that lead to caspase activation. Finally, the proposed studies will shed light on the function of caspases in non-apoptotic pathways.Read moreRead less
Australian Drosophila Biomedical Research Support Facility
Funder
National Health and Medical Research Council
Funding Amount
$1,008,895.00
Summary
Breakthroughs in biomedical research frequently come from the study of model organisms, one of the most important of which is the vinegar fly, Drosophila melanogaster. In Australia, Drosophila is used in biomedical research with a particular focus on understanding processes that result in human cancer or are associated with birth defects or inherited diseases. Drosophila-based research is funded by bodies such as the Anti-Cancer Foundation, the National Health and Medical Research Council (NH an ....Breakthroughs in biomedical research frequently come from the study of model organisms, one of the most important of which is the vinegar fly, Drosophila melanogaster. In Australia, Drosophila is used in biomedical research with a particular focus on understanding processes that result in human cancer or are associated with birth defects or inherited diseases. Drosophila-based research is funded by bodies such as the Anti-Cancer Foundation, the National Health and Medical Research Council (NH and MRC) and the National Institutes of Health of the USA. This proposal seeks to establish infrastructure support for Drosophila research in the form of a central collection of key research stocks, a centralized facility for the importation of genetically defined stocks and a facility for the generation of transgenic Drosophila for use in biomedical research.Read moreRead less
The Mechanism By Which Apical-basal Polarity Complexes Regulate The Salvador-Warts-Hippo Pathway
Funder
National Health and Medical Research Council
Funding Amount
$540,099.00
Summary
Cancer is a multi-hit process involving the activation of critical signaling pathways leading to increased proliferation, survival and increased invasion-metastasis. We have discovered that a neoplastic tumour suppressor gene, lgl, acts though the Salvador-Warts-Hippo (SWH) tumour suppressor pathway to inhibit cell proliferation and cell survival. Here we use the model organism, Drosophila, and mammalian epithelial cells to determine the mechanism by which Lgl activates the SWH pathway.