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.
Defining The Role Of The Novel Gene MUL1 In Antiviral Innate Immunity
Funder
National Health and Medical Research Council
Funding Amount
$511,596.00
Summary
Uncontrolled immune responses can clinically manifest in chronic inflammatory disorders. Viral infections carry a significant global health burden, causing acute and chronic inflammation. This study will characterize a novel regulator of anti-viral immune responses. Understanding the regulation of infection models may provide the means of manipulating immune responses to control infections and provide better health outcomes.
Interferon Regulatory Factor 6: A Novel Epithelial-specific Regulator Of Mucosal Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$517,989.00
Summary
Epithelial cells lining the respiratory and gastrointestinal tracts play pivotal roles in protecting us from infection. Inflammatory factors released by epithelial cells are important for fighting infection; however, they also contribute to chronic inflammatory diseases. We aim to understand how a protein called IRF6 regulates the inflammatory response of epithelial cells. The knowledge gained will identify new therapeutic approaches for inflammatory diseases.
After infection with viruses, parasites and bacteria the protein SerpinB2 becomes very abundant in macrophages, which are white blood cells involved in inflammation. Unfortunately, what this protein is doing is very unclear. We have found that macrophage SerpinB2 dampens the responses of other immune cells. This grant aims to determine how this is achieved and thereby help resolve the role of this protein in a number of diseases such as cancer, lupus, asthma and pre-eclampsia.
Diabolic Regulation Of Macrophage Cell Death Pathways By Legionella
Funder
National Health and Medical Research Council
Funding Amount
$616,912.00
Summary
The bacterial pathogen Legionella causes fatal pneumonia in immuno-compromised humans. Infections depend on a sophisticated secretion machinery that translocates hundreds of proteins into host cells. These proteins subvert several essential defense pathways, including cell death signals. This project will highlight how Legionella interfere with cell death pathways and control the survival of its host cells. These findings will facilitate the development of promising new anti-bacterial agents.
Mechanism Of Proteotoxic Stress Induced Type I Interferon Signalling And Implications For Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$322,952.00
Summary
All cells have a proteasome system to degrade unwanted proteins. Proteasome dysfunction causes a build-up of proteins that triggers, through an unknown mechanism, activation of the immune system leading to inflammation. People with mutations in genes which code for proteasome activity experience a severe disease known as Proteasome-Associated Autoinflammatory Syndrome. We aim to elucidate the link between protein aggregation and immune activation and employ this knowledge in disease treatment.
Interleukin-1β Biology: Mechanisms Of Regulation, Activation And Secretion
Funder
National Health and Medical Research Council
Funding Amount
$641,979.00
Summary
The protein called intelreukin-1 (IL-1) is required to fight off invading pathogens but more recently has been implicated as contributing to diverse diseases characterised by excessive inflammation, such as arthritis, gout, atherosclerosis and even cancer. This project aims to understand how IL-1 is made within cells and then activated to cause inflammation, which will enable these processes to be therapeutically targeted.
Molecular Dissection Of Aberrant IL6/gp130 And TGF? Signaling In The Pathogenesis Of Interstitial Pneumonitis
Funder
National Health and Medical Research Council
Funding Amount
$590,009.00
Summary
Interstitial pneumonia (IP) is frequently observed in the group of lung diseases which affect the transfer of oxygen from inhaled air into the bloodstream. Current treatments for these diseases only effectively manage patient’s symptoms but don’t cure patients of IP. We have developed a strategy to identify the exact cell type responsible for an acute IP and the molecular intermediates that may offer novel treatments and pave the way for a possible cure for this disease.
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.