Macrophages are white blood cells that provide front line defence against infection by initiating inflammatory responses by ingesting or phagocytosing microbes and by releasing soluble messengers (cytokines) to recruit other immune cells. These defensive functions require extensive trafficking of proteins within the macrophages. Protein trafficking is orchestrated in part by a family of membrane fusion proteins called SNAREs. By defining the relevant SNAREs, we have recently discovered a much ac ....Macrophages are white blood cells that provide front line defence against infection by initiating inflammatory responses by ingesting or phagocytosing microbes and by releasing soluble messengers (cytokines) to recruit other immune cells. These defensive functions require extensive trafficking of proteins within the macrophages. Protein trafficking is orchestrated in part by a family of membrane fusion proteins called SNAREs. By defining the relevant SNAREs, we have recently discovered a much acclaimed and novel pathway that allows efficient, combined cytokine secretion and phagocytosis in macrophages. Our studies proposed here will now expand on this discovery by comparing the phagocytic process, in terms of SNARE-mediated membrane and cytokine trafficking, for a wide range of microbes, highlighting differences that could provide new avenues for drug development. Moreover, since our strategy of using SNAREs to investigate and map trafficking pathways has proven so successful, we will now launch a major large-scale initiative to study ALL SNARE-mediated trafficking pathways in macrophages using a discovery pipeline of assays, including live cell imaging, we have developed. This will provide valuable information on many SNAREs including those associated with disease, and will elucidate trafficking pathways governing all macrophage actions in immunity, including cytokine secretion and antigen presentation. All of these pathways are highly relevant to current drug targets being used clinically or studied in inflammatory disease and for the development of vaccines.Read moreRead less
Cell Surface Mucins In Gastrointestinal Infection, Inflammation And Cancer Development
Funder
National Health and Medical Research Council
Funding Amount
$469,627.00
Summary
Cell surface mucins are protective molecules that line all the wet surface of the body, including the gastrointestinal tract. Our research has uncovered that mucins regulate cell growth and cell death. Inappropriate control by the mucins, could lead to chronic inflammation and formation of cancers. We will test how important these molecules are in the development of cancers in the intestine, and further explore the mechanism of action.
Evolution And Function Of A Novel Lateral Flagellar Locus, Flag-2, In Pathogenic Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$465,158.00
Summary
This project will study how the bacteria that cause infant diarrhoea colonize the intestine and induce disease. We have identified a novel genetic region that allows E. coli to survive and persist in the intestine. Similar genes are also present in closely related organisms. This project will help us to undestand how new diseases evolve and emerge and may lead to the development of new vaccines to protect against infant diarrhoea.
Patterns, Pathways And Price Of Developing Disparities In Cardiovascular And Respiratory Health By Age 11-12 Years: The Longitudinal Study Of Australian Children
Funder
National Health and Medical Research Council
Funding Amount
$3,290,912.00
Summary
Cardiovascular and lower respiratory diseases are leading causes of death, show marked social gradients, and have origins in early life. We will measure cardiorespiratory health at age 11-12 years in the national Longitudinal Study of Australian Children. Combined with rich existing psychosocial and health data spanning the entire first decade, we will explore early-life mechanisms underlying emerging patterns of social disparity and their potentially-avoidable cost – evidence that is essential ....Cardiovascular and lower respiratory diseases are leading causes of death, show marked social gradients, and have origins in early life. We will measure cardiorespiratory health at age 11-12 years in the national Longitudinal Study of Australian Children. Combined with rich existing psychosocial and health data spanning the entire first decade, we will explore early-life mechanisms underlying emerging patterns of social disparity and their potentially-avoidable cost – evidence that is essential to develop new intervention strategies.Read moreRead less
Novel Insights Into The Mechanisms Of How Chikungunya Virus Cause Disease In Humans
Funder
National Health and Medical Research Council
Funding Amount
$554,808.00
Summary
Many of the most dangerous and easily transmitted infectious agents are viruses. The emergence of chikungunya virus globally and the recognition of this pathogen in the aetiology of chronic diseases show the need for a better understanding of how the virus cause disease. The expected outcomes are a better understanding of human alphaviral diseases, with a view to improving prevention and treatment strategies to reduce the disease burden of CHIKV and related viruses.
Dissecting The Great Ophthalmic Masquerade: The Global Giant Cell Arteritis Genomics Consortium.
Funder
National Health and Medical Research Council
Funding Amount
$583,269.00
Summary
Giant cell arteritis (GCA) is the most common form of vasculitis in people over 50 years of age. If untreated it can cause catastrophic complications including blindness, though this can be prevented if treated early. Although there is clear evidence for a role of genetic factors in GCA, these have been little studied. We have established an Australian-led International consortium, with clinical, basic science and statistical expertise to thoroughly investigate this devastating disease.
Modulating Inflammatory And Fibrogenic Pathways In Kidney Disease Using A Novel Antagonist Of Protease-Activated-Receptor-2
Funder
National Health and Medical Research Council
Funding Amount
$581,116.00
Summary
Chronic kidney disease (CKD) now affects 10% of adults in industrialised countries. Current treatments are largely ineffective. Thus developing better CKD treatments will have substantial public health benefit. Three well established and clinically relevant animal models of kidney disease will be used to test the ability of a new experimental anti-inflammatory drug, developed by members of this research team at The University of Queensland, to prevent or lessen the progression of CKD.
Macrophage Polarisation And Control Of Pulmonary Inflammation.
Funder
National Health and Medical Research Council
Funding Amount
$895,494.00
Summary
As key immune cells, macrophages are polarised to phenotypes that turn inflammation on or off. In cystic fibrosis, defective macrophage polarisation enhances inflammation and prevents lung repair. We are defining the molecules and cellular pathways that control this process and identifying targets for existing drugs that can be used to reprogram macrophages and restore lung repair to improve patient outcomes.
Understanding How Azithromycin Prevents Exacerbations In Severe Asthma
Funder
National Health and Medical Research Council
Funding Amount
$697,273.00
Summary
In some people with severe asthma, conventional inhaler treatments are not able to control the disease so there is a need for new treatment options. We have recently completed a large clinical trial which showed that very low doses of a common antibiotic help prevent asthma attacks in this situation. However, not much is known about how the antibiotic is working. This study will help us understand how the antibiotic is working and which people respond best.
A New Master Adaptor Protein For Toll-like Receptor Signalling
Funder
National Health and Medical Research Council
Funding Amount
$869,288.00
Summary
Certain proteins on the surface of cells are able to sense danger and infection. These receptors use adaptor proteins to enable cells to respond appropriately. We have discovered a new adaptor that controls receptor signalling in inflammation. This new master adaptor likely has widespread roles in infection and inflammation. We aim to understand how this adaptor works, and to identify ways of blocking its actions. These studies may help us to control inflammation underpinning many diseases.