Mapping The TNF Pathway: A Qualitative And Quantative Molecular Analysis Of The Components And Post-translational Modifications Involved In Physiological And Pathological TNFR1 Signalling
Funder
National Health and Medical Research Council
Funding Amount
$636,258.00
Summary
TNF is a master regulator of the inflammation response and dysregulated TNF signalling causes many human diseases. We will use a cutting edge mass spectrometry technique that we have developed to analyse molecules required for TNF signalling. Understanding how the TNF signalling works in all cell types and with different forms of ligands will open up therapeutic opportunities to selectively target TNF signalling in inflammatory diseases, such as Rheumatoid Arthritis and Cancer.
The Role Of Necroptosis In Inflammatory Skin Diseases
Funder
National Health and Medical Research Council
Funding Amount
$548,690.00
Summary
Diseases associated with exaggerated inflammation account for a large toll of human disease. We have recently described how mice with a mutation in the Sharpin gene, that causes the chronic proliferative dermatitis phenotype (cpdm), can be rescued by crossing these mice to TNF (Tumor Necrosis Factor) knock-out mice. Our findings suggest that TNF induced cell death, rather than TNF induced cytokine production, may be at the root of many inflammatory diseases and we aim to test this hypothesis in ....Diseases associated with exaggerated inflammation account for a large toll of human disease. We have recently described how mice with a mutation in the Sharpin gene, that causes the chronic proliferative dermatitis phenotype (cpdm), can be rescued by crossing these mice to TNF (Tumor Necrosis Factor) knock-out mice. Our findings suggest that TNF induced cell death, rather than TNF induced cytokine production, may be at the root of many inflammatory diseases and we aim to test this hypothesis in this proposal.Read moreRead less
Elucidating The Mechanism And Function Of Extracellular Vesicle Formation During Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
In humans, billions of cells will die daily as part of normal turnover in various organs. It is vital that dying cells are rapidly removed as their accumulation has been linked to autoimmunity and inflammation. To aid efficient removal of dead cells, dying cells can disassemble into smaller fragments for neighbouring cells to engulf. We aim to understand the machinery that control how dying cells can disassemble into smaller pieces and their function in efficient cell clearance and autoimmunity.
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.
The Role Of Necroptosis In Development, The Immune System And Autoimmune Pathology
Funder
National Health and Medical Research Council
Funding Amount
$454,105.00
Summary
Programmed cell death plays critical roles in development and cell-turnover in the adult. Defects in this process can cause cancer or autoimmune diseases. We will use genetic and biochemical approaches to define the individual roles of necroptosis, a newly described cell death process, and those overlapping with apoptosis in normal development and cell-turnover as well as in cancer and autoimmune diseases. The objective of this work is to identify potential targets for therapeutic intervention i ....Programmed cell death plays critical roles in development and cell-turnover in the adult. Defects in this process can cause cancer or autoimmune diseases. We will use genetic and biochemical approaches to define the individual roles of necroptosis, a newly described cell death process, and those overlapping with apoptosis in normal development and cell-turnover as well as in cancer and autoimmune diseases. The objective of this work is to identify potential targets for therapeutic intervention in cancer or immunopathology.Read moreRead less
Investigating The Contribution Of Distinct Mitochondrial Cell Death Pathways To Platelet Survival And Function
Funder
National Health and Medical Research Council
Funding Amount
$635,247.00
Summary
Platelets are small blood cells that form clots to stop bleeding. We have found new and unexpected roles for 2 distinct pathways that regulate cell death in the process of blood clot formation. We will study the precise role of these pathways in blood clot formation, and determine whether they may also regulate the survival of platelets stored by the blood bank for transfusion. These studies will provide new insight into the role of cell death pathways in blood clot formation, and may help to im ....Platelets are small blood cells that form clots to stop bleeding. We have found new and unexpected roles for 2 distinct pathways that regulate cell death in the process of blood clot formation. We will study the precise role of these pathways in blood clot formation, and determine whether they may also regulate the survival of platelets stored by the blood bank for transfusion. These studies will provide new insight into the role of cell death pathways in blood clot formation, and may help to improve current protocols for storing plateletsRead moreRead less
Understanding The Activation Of Pro-apoptotic Bcl-2 Family Proteins For The Development Of Modulators Of Apoptosis
Funder
National Health and Medical Research Council
Funding Amount
$627,805.00
Summary
Programmed cell death is a process by which the body protects against rogue cells, eg cells potentially cancerous or infected by viruses. Dysregulation of the process occurs in cancer and can also lead to degenerative diseases. This work will discover the molecular mechanisms by which key proteins control the life/death switch in cells and will develop compounds capable of regulating their activity, setting the foundation for developing therapeutics aimed at regulating these processes.
What Is The Molecular Mechanism Underlying Cell Death By Necroptosis?
Funder
National Health and Medical Research Council
Funding Amount
$653,742.00
Summary
Recently, we and others have demonstrated that part of the MLKL protein is able to kill cells. This process is known to cause a number of pathologies, including those arising from stroke. Blocking this type of cell death has thus emerged as an attractive therapeutic strategy. However, precisely how MLKL kills cells remains unclear and controversial. In this project, we will resolve these controversies with the goal of an increased fundamental understanding to aid drug discovery.