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
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
Defining The Molecular Regulators Of Apoptotic Cell Disassembly And Their Role In Cell Clearance And Lupus-like Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$773,848.00
Summary
In humans, billions of cells will die daily as part of normal turnover in various organs. It is vital that dying cells are rapidly removed as their accumulation has been linked to autoimmunity and inflammation. To aid efficient removal of dead cells, dying cells can disassemble into smaller fragments for neighbouring cells to engulf. We aim to understand the machinery that controls how dying cells can disassemble into smaller pieces and their function in cell clearance and autoimmunity.
Elucidating The Mechanism And Function Of Cell Disassembly During Apoptosis
Funder
National Health and Medical Research Council
Funding Amount
$425,048.00
Summary
In humans, billions of cells will die daily in various organs as part of normal turnover and disease progression. During cell death, dying cells can disassembly in to smaller fragments, a process that could facilitate their removal, as well as mediate communication with other healthy cells. I aim to understand the machinery that control how dying cells can disassemble into smaller pieces and their function in influenza A infection.
Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, ....Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, particularly in cells from the brain. Our recent studies indicate that this mitochondrial pool of glutathione is particularly important in limiting the death of cells from the brain when exposed to damaging substances that are increased in some diseases. Thus, the capacity of mitochondrial glutathione to deal with such substances might be a factor in determining the extent of cell loss in the brain, which is an important determinant of symptoms in some of the major neurological diseases. Consistent with this possibility, we have obtained evidence indicating that decreases in glutathione in the mitochondria contribute to the cell death and brain damage that results from a stroke. In our proposed studies, we will investigate the function of mitochondrial glutathione in the two major cell populations from the brain, neurons and astrocytes. We will characterise the protective role of the glutathione and investigate how it enters the mitochondria and what factors influence the amount that is present. This will provide new insights into the function of glutathione in the mitochondria and could also suggest novel approaches for manipulating this antioxidant pool. We will also study models of stroke and some related brain disorders to more directly test the role of this antioxidant in disease and to assess whether manipulating the content of glutathione in the mitochondria has the potential to reduce damage and improve function in these disordersRead moreRead less
Molecular Mechanisms Of Death In Cells With Defective Apoptotic Pathways
Funder
National Health and Medical Research Council
Funding Amount
$335,065.00
Summary
The body protects itself from cancer by killing any cell that poses a risk of becoming a tumour. The body kills these cells via a carefully orchestrated sequence (or pathway) of events, however many cancer cells have defects in cell death pathways that has permitted them to survive even though they have been told to die. In this proposal we set out a research program to investigate how to kill cancer cells that don't want to die. Various tumour cells have been shown to have increased levels of B ....The body protects itself from cancer by killing any cell that poses a risk of becoming a tumour. The body kills these cells via a carefully orchestrated sequence (or pathway) of events, however many cancer cells have defects in cell death pathways that has permitted them to survive even though they have been told to die. In this proposal we set out a research program to investigate how to kill cancer cells that don't want to die. Various tumour cells have been shown to have increased levels of Bcl-2, a proto-oncogene that blocks cell death induced by diverse stimuli. Cells that over-express Bcl-2 are also resistant to cytotoxic drugs. Understanding how to bypass Bcl-2 (or proteins that block cell death in tumours) will lead to a better understanding of cell death-cell survival and allow us to explore the possibility of tailoring treatment for patients in which specific defects in death pathways have been identified in their cancer cells. Cytotoxic lymphocytes (CL) are cells of the immune system that defend the body from cancer by specifically attacking and killing tumor cells. We have been pioneering studies of CL:tumour interactions in which we can define the morphology and kinetics of critical events in cell death and have shown that CL have the ability to kill target cells that over-express Bcl-2. Following the aims in this proposal, we will understand the mechanisms by which cytotoxic lymphocytes kill target cells that have defects in classical cell death pathways. These studies will therefore define alternative pathways to cell death in the event that a key component of the preferential pathway to cell death is inoperative. Since cytotoxic lymphocytes use a variety of ways to kill their targets and tumors may contain multiple defects in cell death pathways, we will explore which are the key defects, or the combination of multiple defects, in cell death pathways that prevent cytotoxic lymphocyte mediated cell death and permit tumour survival in vivo.Read moreRead less
Characterisation Of The Tumour Suppressor Function Of Caspase-2
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
Aberrant cell death (apoptosis) is associated with many diseases including cancer. Apoptosis is mediated by a group of enzymes called caspases. Recently we have discovered that one of these enzymes, caspase-2, acts as a tumour suppressor. We now wish to validate this finding in several preclinical models of cancer and understand precisely how caspase-2 works to safeguard cells against cancer development. These studies will help better understand cancer and ways to treat it.