Regulation Of Extrinsic Death Pathways In Neutrophils
Funder
National Health and Medical Research Council
Funding Amount
$84,656.00
Summary
During infection, the lifespan of neutrophils normally increases despite an abundance of neutrophil death signals in inflamed tissues. Altered lifespan of neutrophils has been reported in diseases associated with influenza, Streptococcus, RSV and cytomegalovirus infection. Our research has discovered a relationship between the two dominant death pathways in neutrophils, indicating that alterations in one death pathway protect the neutrophil from death signals from the second death pathway.
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.
Regulation And Mechanisms Of Cell Cycling, Cell Senescence And Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$876,005.00
Summary
Most of our cells are not dividing, but persist in a stable arrested state, yet little is known of the molecular mechanisms that regulate and maintain permanent arrest, or that go wrong when cells start proliferating and turn into cancers. This proposal addresses an area of fundamental, basic biology, that has been largely overlooked. A better understanding of the molecules that regulate cell stability might provide new drug targets so that tumour cell proliferation can be stopped.
Exploring The Inflammatory Signature Of The Anti-cancer Smac-mimetic, Birinapant, And The Contribution Of This Signature To Birinapant Anti-Tumour Activity
Funder
National Health and Medical Research Council
Funding Amount
$192,322.00
Summary
Programmed cell death (PCD) is an essential process for the removal of cancer cells. Defects in PCD are now known to be a causal factor in cancer initiation and chemotherapeutic resistance. Proteins called IAPs protect cancer cells from PCD, however, inhibitors of IAPs have been developed to kill cancer cells in this respect. Indeed, IAP inhibitors can also promote inflammation, which may improve or hamper their efficacy in killing cancer cells, an issue we now wish to explore and exploit.
Modulating Inflammation As A Therapy For Harlequin Ichthyosis
Funder
National Health and Medical Research Council
Funding Amount
$718,739.00
Summary
Harlequin Ichthyosis is a severe inherited skin disease caused by mutations in a protein which regulates how skin cells control their levels of lipids. Treatments for this disease are limited and do little to improve patients condition. We believe we have found a new way to treat this condition by altering tissue inflammation. This grant will undertake important experiments aimed at developing new therapies for this currently incurable disease.
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.
Glucose Toxicity-induced Activation Of The Bcl-2-regulated Apoptotic Pathway In Pancreatic Beta Cells
Funder
National Health and Medical Research Council
Funding Amount
$617,238.00
Summary
High blood glucose or hyperglycaemia is a feature of type 2 diabetes. Hyperglycaemia and fatty acids in the blood can cause damage of the insulin-producing pancreatic beta cells, resulting in worsening of diabetes. We plan to elucidate the pathways in beta cells that are stimulated by high levels of glucose and fatty acids, and to determine if these pathways are turned on in the pancreas of patients with type 2 diabetes, to try and identify targets for new therapies.
The C-type Lectin Mincle Exemplifies A New Mode Of Sterile Inflammation In Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$609,237.00
Summary
This project investigates two of the life-changing cardiovascular events that most commonly impact on Australians today; Heart attack and Stroke. These diseases often leave individuals debilitated with a long recovery period, and for many people the event is fatal. We have shown that blocking the action of an immune component, "Mincle", reduces the inflammation associated with stroke, and improves recovery. This project looks at what Mincle does in brain and heart muscle, and why blocking Mincle ....This project investigates two of the life-changing cardiovascular events that most commonly impact on Australians today; Heart attack and Stroke. These diseases often leave individuals debilitated with a long recovery period, and for many people the event is fatal. We have shown that blocking the action of an immune component, "Mincle", reduces the inflammation associated with stroke, and improves recovery. This project looks at what Mincle does in brain and heart muscle, and why blocking Mincle protects cells from loss of oxygen.Read moreRead less
Regulation Of TNF Expression In Inflammation And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$728,447.00
Summary
By studying a spontaneous mutation in mice, we have found an error in the TNF gene (a major factor in many inflammatory diseases) that causes severe arthritis, heart valve disease and gut inflammation. We have also identified new regulators of TNF expression, which might be useful therapeutic targets to limit inflammation. We intend to study the role of these regulators in controlling the expression of TNF, and the link between chronic inflammation and the development of 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