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.
Viral Interference With Apoptosis: Defining The Mechanisms And Effects On Viral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$551,328.00
Summary
Apoptosis, or programmed cell death, is an orderly process whereby unwanted or damaged cells are removed from an organism. Deregulation of apoptosis has been implicated in the development of diseases such as cancer and autoimmunity. Therefore, a precise understanding of the mechanisms controlling the initiation of apoptosis has important clinical implications. In addition to removing unwanted cells, apoptosis functions as a defence mechanism to inhibit viral replication. Hence, in order to repli ....Apoptosis, or programmed cell death, is an orderly process whereby unwanted or damaged cells are removed from an organism. Deregulation of apoptosis has been implicated in the development of diseases such as cancer and autoimmunity. Therefore, a precise understanding of the mechanisms controlling the initiation of apoptosis has important clinical implications. In addition to removing unwanted cells, apoptosis functions as a defence mechanism to inhibit viral replication. Hence, in order to replicate efficiently viruses have evolved means to inhibit or interfere with apoptosis. The central aim of this work is to understand how two genes encoded by murine cytomegalovirus (MCMV) inhibit apoptosis and contribute to viral replication. MCMV is used as a model for human CMV (HCMV) infection. The majority of the human population is infected with HCMV which poses no risk to healthy individuals. However, reactivation of HCMV in people who are immunosuppressed such as transplant recipients or AIDS patiens is a significant cause of mortality. The MCMV infection model has provided important insights as to how the immune system controls infection and the mechanisms utilized by viruses to circumvent these processes. The proposed studies will improve our understanding of the processes that regulate viral replication. Understanding how viruses subvert host defence mechanisms will allow us to better understand their role in causing human disease, and thus, will provide key information for the design of improved anti-viral strategies. Importantly, the type of analyses proposed here will also contribute critical insights into the normal processes that control cell survival.Read moreRead less
Regulation Of Autoimmunity By Non-apoptotic Caspases
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Excessive cell death can lead to chronic inflammation and autoimmunity. Cells can die by different mechanisms including necroptosis which causes inflammation, and apoptosis which does not. Recent studies show that caspases, a component of the apoptosis pathway which accelerate cell death, also prevent immune activation by dying cells. I will investigate whether caspases contribute to autoimmune disease and whether caspases can dampen the inflammation that occurs during necroptotic cell death.
The pathology of many acute and chronic diseases associated with the inappropriate activation of genetically encoded programmed cell death pathways, such as sepsis, stroke, diabetes and neurodegeneration, is linked to detrimental inflammation. This project will accurately define at the molecular level how programmed cell death triggers inflammatory responses, and use this knowledge to test novel and next-generation therapeutic strategies in inflammatory-driven diseases.
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.
Mechanisms Of Cell Death Driven Inflammation In The Skin
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
Inflammatory skin conditions are a leading cause of disease. Current therapies treat symptoms not causes of inflammation. Skin cells constantly interact with cells of the immune system, and with a diverse array of helpful and harmful microorganisms. My data suggest a role of the skin flora and resident immune cells in the initiation and progression of skin disease. I will investigate how the microbiota and immune cells can initiate cell death and drive excessive immune responses in the skin.
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.