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.
Understanding The Role Of Caspase-2 In Cellular Stress Response And Ageing
Funder
National Health and Medical Research Council
Funding Amount
$918,517.00
Summary
This project builds upon our recent findings showing that a protein, called caspase-2, is involved in protecting against oxidative damage and ageing in a mouse model. We propose to carry out further studies to fully understand how caspase-2 regulates cell’s response to oxidative stress. Such studies will be critical in assessing if caspase-2 or its substrates are useful targets for drugs to treat diseases that may arise due to cell’s inability to properly respond to oxidative damage.
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.
Interleukin-1β Biology: Mechanisms Of Regulation, Activation And Secretion
Funder
National Health and Medical Research Council
Funding Amount
$641,979.00
Summary
The protein called intelreukin-1 (IL-1) is required to fight off invading pathogens but more recently has been implicated as contributing to diverse diseases characterised by excessive inflammation, such as arthritis, gout, atherosclerosis and even cancer. This project aims to understand how IL-1 is made within cells and then activated to cause inflammation, which will enable these processes to be therapeutically targeted.
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.
Targeting Caspase 8 In T-Cell Homeostasis And Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,215,780.00
Summary
Chronic infectious diseases such as HIV, hepatitis B and tuberculosis impose a massive global health burden and new treatments are desperately needed. This proposal investigates a new approach to improve immune responses and clear chronic infections. Our multidisciplinary team will define the molecular and cellular biology underlying this approach and translate our findings by re-purposing a drug already approved for other indications in humans.
As the first recruited cells, neutrophils direct protective responses against infection, but can also mediate destructive responses in inflammatory disease. This project will determine mechanisms driving neutrophil-dependent inflammation in both settings, by examining a specific inflammation-promoting molecular pathway (the ïinflammasomeÍ) in neutrophils. This research will lead to a better understanding of inflammation, and may suggest therapeutics for treating inflammatory disease.
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.
Microbial Evasion Of A Novel Inflammasome By Salmonella
Funder
National Health and Medical Research Council
Funding Amount
$486,174.00
Summary
Microbes quickly evolve to evade detection by the innate immune system, the body’s first line of defence against infection. This project investigates the mechanisms by which the immune system recognises bacterial infection, and pathways used by bacteria to avoid these defences. This research will lead to a better understanding of mechanisms underlying resistance and susceptibility to bacterial infection.