Deadly Commute - Targeting The Trafficking Mechanisms That Licence Inflammatory Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$774,544.00
Summary
MLKL is a protein naturally found inside cells. MLKL is activated by inflammation. Once activated, MLKL relocates to the outer periphery of cells and kills them. Gut cells are especially vulnerable to death-by-MLKL and this problem causes Inflammatory Bowel Disease. Using cutting edge microscopy, we have discovered how MLKL moves to the periphery of cells prior to killing them. We will test if blocking this movement of MLKL to the cell periphery stops gut death and Inflammatory Bowel Disease.
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.
Tipping The Inflammatory Response Of TNF In Favour Of Death
Funder
National Health and Medical Research Council
Funding Amount
$660,403.00
Summary
Cancer cells promote their own growth by exploiting the body’s natural defence. This natural defence is termed inflammation and cancer cells utilise inflammation to grow and metastasise. We have identified two exciting proteins that are required for cancer cells to stay alive. Under conditions that drive inflammation, if we remove these proteins cancer cells now activate their death signals and die. Our discovery provides new opportunities on fundamental ways by which cancer cells can be killed.
Molecular Targeting Of Innate Immune Signalling Pathways In Cancer And Auto-Inflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$753,300.00
Summary
To achieve an accurate molecular understanding of innate immune system receptor signalling, both intracellularly and in whole organisms, in health and disease. This knowledge will then be used to generate better treatments for the extensive range of human diseases that are caused or exacerbated by dysfunctional innate immune signalling, including Crohn's disease, psoriasis and cancer.
This application describes a research proposal that will achieve an accurate molecular understanding of innate immune system receptor signalling in health and disease. This knowledge will then be used to generate better treatments for the extensive range of human diseases that are caused or exacerbated by dysfunctional innate immune signalling, including Crohn's disease, psoriasis and cancer.
The Splanchnic Anti-inflammatory Pathway: The Real Inflammatory Reflex
Funder
National Health and Medical Research Council
Funding Amount
$613,466.00
Summary
The brain strongly influences immune function through a neural reflex: the inflammatory reflex. This reflex was recently revised and a new model for its efferent arm, in stark contrast with the existing version, was proposed: the motor pathway of this reflex is purely sympathetic and travels through the splanchnic nerves. The aim of this project is to define the peripheral and central neural pathway of this reflex. Future improvements in health and medical knowledge will follow
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
Investigating The Roles Of Non-coding RNAs In Inflammatory Signalling And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$408,768.00
Summary
Inflammation occurs as part of the body's natural defenses against infection or injury, but can be damaging when unregulated and can lead to cancer. Although the protein factors critical for inflammation have been carefully studied it remains unknown how ribonucleic acid (RNA) molecules can modify and regulate inflammation. This project will identify RNA molecules that control inflammatory signalling, and further translate these findings to show they contribute to the progression of cancer.
Pathophysiological Significance Of Reverse Signaling Through Membrane TNF
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surfac ....Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surface of the cell and then it is 'clipped off' and released as a smaller, soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We believe that binding of tumour necrosis factor receptors to the cytokine while it is in its membrane form can also send a message backwards, into the cell bearing the tumour necrosis factor. This process, known as reverse signalling, then changes the activity of this cell. In this project we will investigate this phenomenon in detail. The results will be extremely relevant to new methods of treatment of diseases, that rely either on 'masking' tumour necrosis factor by administering soluble forms of its receptor or on blocking the release of the soluble form of the molecule from the surface of the cell. Our work will enable us to understand the consequences of these approaches more fully. We will also be looking at the role of the membrane form of tumour necrosis factor in a model of infectious disease. Influenza virus is responsible for a great deal of morbidity and mortality around the world. We, and others, have shown, in a mouse model, that some cells in the lungs make tumour necrosis factor during the course of viral pneumonia. Here we will determine whether the membrane form of this cytokine plays a role in clearing virus or causing some of the complications of this disease. This also may have relevance to other inflammatory and infectious disease.Read moreRead less
New Drug Combinations To Enhance Elimination Of Hepatitis B Infection
Funder
National Health and Medical Research Council
Funding Amount
$888,304.00
Summary
We have developed a therapy that kills hepatitis B virus infected cells and promotes elimination of infection. We are now testing novel drugs that can be used to maximise the efficacy of our new treatment to promote better outcomes that may be translated to other infections.