Mechanisms Of Mcl-1- And Bcl-2-mediated Resistance To Apoptosis
Funder
National Health and Medical Research Council
Funding Amount
$439,796.00
Summary
Anti-cancer therapies that target either the mitochondrial or death receptor pathways of apoptotic cell death are being developed and in clinical trials. In certain cancer cells, the tBid protein links the two pathways, making the death receptor pathway dependent on the mitochondrial pathway. Our studies will test how tBid links the two pathways and how the link might be bypassed, potentially indicating means of improving the effectiveness of treating cancer by targeting death receptors (e.g. TR ....Anti-cancer therapies that target either the mitochondrial or death receptor pathways of apoptotic cell death are being developed and in clinical trials. In certain cancer cells, the tBid protein links the two pathways, making the death receptor pathway dependent on the mitochondrial pathway. Our studies will test how tBid links the two pathways and how the link might be bypassed, potentially indicating means of improving the effectiveness of treating cancer by targeting death receptors (e.g. TRAIL).Read moreRead less
In cancer cells the normal process of cell death (called apoptosis) is defective, helping abnormal cells to grow and multiply unchecked. The Bak protein is a member of the Bcl-2 family of apoptosis regulators, and plays a pivotal role in mediating cell death. By defining each step in Bak-mediated apoptosis, we aim to better understand how cancer cells accumulate, and how targeting the Bcl-2 family may lead to effective anti-cancer therapeutics.
Role Of Bak And Bax Membrane Anchors In Targeting And Apoptotic Pore Formation.
Funder
National Health and Medical Research Council
Funding Amount
$352,319.00
Summary
In cancer cells the normal process of cell death (called apoptosis) is defective, helping abnormal cells to grow and multiply unchecked. The Bak and Bax proteins are members of the Bcl-2 family of apoptosis regulators, and play a pivotal role in mediating cell death. By defining how these proteins form a pore in mitochondria, the point of no return in cell death, will help the development of novel anti-cancer agents that target the Bcl-2 family in general, and Bak and Bax in particular.
Deciphering Activation Of The Apoptotic Cell Death Program
Funder
National Health and Medical Research Council
Funding Amount
$577,109.00
Summary
Apoptosis is the cell death mechanism by which unwanted, damaged or excess cells are removed from the body. It is critical for normal development and immune system function, and is deregulated in a number of diseases including cancer, neurodegeneration and autoimmunity. We shall determine how apoptosis is controlled by a family of proteins called the Bcl-2 family, thereby providing insight for the development of novel therapies.
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
Genetic And Phyisological Regulation Of KIR2DL4 Expression
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
Genetic mutations occur frequently but most are deleterious and are lost from the population. Advantageous mutations are selected for and eventually replace the original gene. However, some mutations are advantageous under one set of circumstances and disadvantageous under others. These mutations often reach a high frequency in the population and are maintained along with the original gene. An example of this situation is the mutation in the haemoglobin gene that causes sickle cell anaemia. A si ....Genetic mutations occur frequently but most are deleterious and are lost from the population. Advantageous mutations are selected for and eventually replace the original gene. However, some mutations are advantageous under one set of circumstances and disadvantageous under others. These mutations often reach a high frequency in the population and are maintained along with the original gene. An example of this situation is the mutation in the haemoglobin gene that causes sickle cell anaemia. A single copy of the mutant gene protects against malaria (advantageous) but a double dose of the gene results in sickle cell anaemia, which is fatal. Both the mutant and original gene are maintained in the population as the number of people dying from sickle cell anaemia is less than the number who would die from malaria if the mutant gene did not exist. This phenomenon is known as balancing selection. There are many examples of balancing selection and for each example there is usually a medical condition associated with a double dose of the mutant gene. We have discovered a new example of balancing selection in one of the genes used by the immune system. Very little is known about the function of this gene. In fact the literature abounds with contradictory findings concerning this gene. Our discovery that a mutant gene is present at very high frequency in the population helps explain these contradictory findings and places us in a very strong position to achieve a much better understanding of the function of this gene. We propose to investigate the basic biology of this gene and how it used in the immune system in order to obtain clues as to which medical condition this mutation may be relevant to.Read moreRead less