Only recently has it emerged that our cells have a built-in backup mechanism that instructs cells to die in extreme cases, such as when viruses have hijacked a cell. A misfiring backup mechanism is thought to underlie a number of human diseases, including inflammatory disease. Our investigation will establish a starting point for the development of novel anti-inflammatory drugs.
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.
Killing Infected Cells As A Mechanism To Eradicate Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$1,085,770.00
Summary
Mycobacterium tuberculosis (Mtb), the causative agent of TB, is rapidly becoming resistant to all antibiotics and this disease kills more than one million people each year. This underscores the urgent need to develop new treatments for this disease. We are developing a therapy that kills Mtb infected cells and may help to eradicate infection. This highly novel approach to the treatment of TB would have profound implications for the 2 billion people infected with this pathogen.
Targeting IAPs In Leukaemias Using The Smac-mimetic Drug Birinapant
Funder
National Health and Medical Research Council
Funding Amount
$969,304.00
Summary
Acute Myeloid Leukaemia (AML) is an aggressive blood cancer. Overall, less than 50% of AML patients are cured. This project evaluates a new drug, Birinapant, in the treatment of AML. Our research will define the AMLs that best respond to Birinapant, and discover combined therapies that will overcome drug resistance. Thus, this project will lead the way towards a clinical trial of Birinapant in AML, focusing on patients who benefit the most and treatments that increase numbers of who may respond.
Bacterial Inhibition Of Cell Signalling And Apoptosis During Gastrintestinal Infection
Funder
National Health and Medical Research Council
Funding Amount
$542,011.00
Summary
E. coli are a major cause of severe diarrhoeal disease. In order to establish infection, E. coli inhibits a host response where cells with bacteria stuck to them are ‘killed off’ and excreted as waste. This recent discovery illuminated an unknown role for cell death in the immune response during bacterial gastroenteritis. This project will study this phenomenon further to better understand the host immune response to infection and also other gut diseases such as inflammatory bowel disease.
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.
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.
Host innate defence relies on the activation of several signalling pathways that regulate inflammation and cell death. Several important bacterial pathogens of humans inject virulence “effector” proteins into infected cells that interrupt host cell signalling pathways. We recently discovered a family of new effector proteins that directly degrade host proteins and block cell death. Here we will characterise this and other members of the family to understand their role during infection.
Unconventional Mechanisms For Activating The NLRP3 Inflammasome
Funder
National Health and Medical Research Council
Funding Amount
$747,031.00
Summary
Many inflammatory driven diseases such as arthritis, atherosclerosis and septic shock are also associated with cell death. This project will identify, at the molecular level, how cell death signalling specifically acts to trigger pathological inflammation. As such, it will identify novel targets for the development of next generation anti-inflammatory drugs.