In a human body, about a million cells are born every second, and a million die by activating a physiological cell death mechanism. If cell death fails to occur, cells accumulate and can develop into cancers. Determining the mechanism and regulation of physiological cell death will provide novel approaches to treat cancers and auto-immune diseases, both of which are characterised by failure of certain cells to die.
Using Mouse Models To Decipher The Function Of Caspase-2 In Limiting Aneuploidy Tolerance And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$871,162.00
Summary
Aneuploidy or abnormal chromosome number is a feature of cancer cells. The extent of aneuploidy is often predictive of prognosis and the effectiveness of cancer treatment. We discovered that a tumour suppressing protein, caspase-2, is important for deleting aneuploid cells that may otherwise become cancerous. In this project we will use cancer models to decipher how caspase-2 safeguards against aneuploidy and cancer to better understand how cancer cells can survive and be targeted for treatment.
Deciphering The Function Of Caspase-2 In DNA Damage Response And Tumour Suppression
Funder
National Health and Medical Research Council
Funding Amount
$808,007.00
Summary
Aberrant cell death and DNA damage response (DDR) are hallmarks of tumourigenesis. Recently we have discovered that an enzyme, caspase-2, previously implicated in cell death execution, also works in DDR and acts as a tumour suppressor. We now wish to validate these finding in preclinical models of cancer and understand precisely how caspase-2 safeguards against cancer development. These studies will help better understand tumourigenesis and may lead to the discovery of new drug targets.
The Role Of Apoptotic Caspases In Regulating Type I Interferon Production
Funder
National Health and Medical Research Council
Funding Amount
$791,746.00
Summary
Type I interferons (IFNs) are potent anti-viral cytokines. Dysregulated type I IFN responses result in major pathologies, e.g., embryonic lethality and defects in tissue homeostasis. We have identified a novel molecular mechanism regulating IFN production that relies on the host’s own apoptotic caspases. We hypothesize that apoptotic caspases critically regulate IFN responses during the process of cell death, with implications for tissue homeostasis and host responses to infection.
Regulation Of Cell Death, Cell Survival And Ubiquitination In Normal Physiology And Disease
Funder
National Health and Medical Research Council
Funding Amount
$851,980.00
Summary
The project will investigate the functions of specific genes and pathways to understand the molecular basis of various diseases. It is based on our data that indicate new roles for (i) cell death in genomic instability in cancer, and (ii) ubiquitination in hypertension, developmental defects, kidney disease, as well as iron homeostasis. The work will lead to new understanding of human disease and discovery of potential new drug targets. It will also provide training of junior scientists.
Focus On Molecular Mechanisms By Which Cells Kill Themselves.
Funder
National Health and Medical Research Council
Funding Amount
$4,366,120.00
Summary
The main aim of this Fellowship is to enable me to further expand, enhance, and strengthen the study of cell death at La Trobe. I wish to establish a centre for bio-medical research at La Trobe that acts collaboratively with local, national and international researchers to conduct basic research and harness the results to develop new therapies. Since moving to La Trobe in January 2006 I have been able to build and expand the critical mass of cell death researchers by recruiting laboratory heads, ....The main aim of this Fellowship is to enable me to further expand, enhance, and strengthen the study of cell death at La Trobe. I wish to establish a centre for bio-medical research at La Trobe that acts collaboratively with local, national and international researchers to conduct basic research and harness the results to develop new therapies. Since moving to La Trobe in January 2006 I have been able to build and expand the critical mass of cell death researchers by recruiting laboratory heads, post-doctoral fellows and several PhD and Honours students. These have joined post-docs, who moved with me from WEHI. We continue to have very close links with the WEHI Cell Death NHMRC Program Grant I remain a Chief Investigator on that grant, renewed in 2006. Because many of the WEHI facilities are on the La Trobe campus at Bundoora, my lab has better access to new mouse strains, monoclonal antibody production, medicinal chemistry, and genetically modified mouse production than those at WEHI in Parkville. This Fellowship will allow me to accelerate the building of a research group that will make substantial collaborative contributions to the basic scientific study of the mechanisms of cell death, to identification of therapeutic targets, to testing and validation of novel pharmaceutical compounds in vitro, and to facilitate clinical trials in Australia. Australian research on the basic mechanisms of cell death is not just of international standard, it is world leading. While it is important that our research is funded to maintain this position, we do not see ourselves as competing with overseas groups, but participating in a joint scientific effort. The translation of basic findings into new treatments will require the input from pharmaceutical industry that Australia lacks. To shorten the time for clinical translation, and to benefit from these developments, we must retain our research credentials, and remain collaboratively integrated with the international effort.Read moreRead less
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.
The balance between cellular survival and death must be tightly regulated. Cells respond to viral infection by self-destructing, thus limiting viral spread to other cells. Viruses have evolved ways to subvert this defensive cell suicide. This project will define and characterise viral factors that maintain host cell survival during infection. These may be targets for the development of new anti-viral therapies and vaccines.
Regulation Of Cell Death, Cell Survival And Ubiquitination In Normal Physiology And Disease
Funder
National Health and Medical Research Council
Funding Amount
$823,008.00
Summary
I am a cellular and molecular biologist with extensive training in a number of biomedical research areas. For over 20 years I have used my training and skills to understand the normal functioning of the body and what molecular and cellular changes underlie various diseases. This fellowship will allow me to continue the groundbreaking work we have been doing to explore the function of several proteins in diseases such as cancer, hypertension, lung inflammation and anaemia.
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