This project will examine new ways in which the major effector cells of allergy migrate to sites of inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma attack. We have identified a potential receptor for this protein on hu ....This project will examine new ways in which the major effector cells of allergy migrate to sites of inflammation, such as the lung and the skin and are activated locally by a novel S100 protein mediator. We have found a natural protein of the innate immune system, present in macrophages and neutrophils in the lungs of patients with acute fatal asthma, which activates mast cells causing release of mediators that trigger asthma attack. We have identified a potential receptor for this protein on human mast cells grown in culture. We will characterise the chemical nature of this receptor and verify that it is functionally important in mast cell activation. Because mast cells reside in almost all body tissues and are also important mediators of host responses to infection and in chronic inflammation such as rheumatoid arthritis and psoriasis, our studies may indicate novel and unexpected ways in which they are activated. Another key cell in allergic and parasitic diseases is the eosinophil. We have found that two other S100 proteins are expressed in eosinophils from the blood of normal individuals and that the genes that encode these proteins are regulated by mediators that regulate eosinophil migration and survival at allergic sites. However although the numbers these cells are high in lung biopsies from patients with asthma, we find that these proteins are generally not expressed. Because one of the S100 proteins, S100A9, was recently found to be important in the ability of other blood cells to migrate to signals that recruit them into tissues, we will examine whether this protein regulates the ability of eosinophils to migrate. Results from this project will provide new knowledge concerning mechanisms of allergy and may lead to the design of novel strategies to regulate the process. Results may have broader ramifications applicable to other inflammatory and infectious diseases.Read moreRead less
New Mechanisms Regulating S100 Protein Function In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$813,929.00
Summary
This project will examine new ways which affect the major effector cells in allergic inflammation and asthma regulated by novel S100 protein mediators. We find a natural protein (S100A12) of the innate immune system, in cells in the lungs of patients with acute asthma. S100A12 activates mast cells to release mediators that trigger asthma attack. We will characterise the proteins with which this protein binds on the cell surface and and determine how this mediates their activation.
This project will examine new ways in which the major effector cells of allergic inflammation and asthma are regulated by novel S100 protein mediators. We find two natural proteins of the innate immune system, present in cells in the lungs of patients with acute asthma. These have apparently opposing activates: one, S100A12, activates mast cells to release mediators that trigger asthma attack. We will characterise how this proteins is regulated in eosinophils, key cells in asthma. Because mast c ....This project will examine new ways in which the major effector cells of allergic inflammation and asthma are regulated by novel S100 protein mediators. We find two natural proteins of the innate immune system, present in cells in the lungs of patients with acute asthma. These have apparently opposing activates: one, S100A12, activates mast cells to release mediators that trigger asthma attack. We will characterise how this proteins is regulated in eosinophils, key cells in asthma. Because mast cells reside in almost all body tissues and are also important mediators of host responses to allergy, infection and in chronic inflammation such as rheumatoid arthritis and psoriasis, our studies may indicate novel and unexpected ways in which they are activated. A second S100 protein (S100A8) is an efficient scavenger of oxidants that can cause damage to the lung. We find both S100A12 and S100A8 that has been modified by oxidants, in sputum from pateints with asthma. In addition to its anti-oxidant effects, S100A8 can downregulate production of some of the inflammatory mediators that promote allergy and asthma. This is an important finding that will help us understand how drugs used in treatment, such as steroids, are acting. We will generate a mouse expressing this protein in its lungs and determine how this affects normal lungs and the course of asthma. If, as we expect, asthma is reduced, we will have found a novel new pathway that is important in the resolution of asthma. Results from this project will provide new knowledge concerning mechanisms of regulation in allergy and asthma and may lead to the design of novel strategies to regulate the process. Results will have broader ramifications applicable to other chronc inflammatory where these proteins are expressed. We have new reagents that could also assist in the diagnosis of these conditions and may be useful for monitoring treatment.Read moreRead less
Inflammation-associated S100 Proteins: Links Between Arthritis And Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$454,691.00
Summary
Deeper understanding of the basic contributions of inflammation to cardiovascular disease can lead to better strategies for treatment and diagnosis. There are shared mechanisms in rheumatoid arthritis and these patients are at significantly higher risk of myocardial infarction and heart failure than the healthy normal population. This project will improve heart health because it will address how newly-recognised proteins, called S100 proteins, mediate pathogenesis and how they are regulated in c ....Deeper understanding of the basic contributions of inflammation to cardiovascular disease can lead to better strategies for treatment and diagnosis. There are shared mechanisms in rheumatoid arthritis and these patients are at significantly higher risk of myocardial infarction and heart failure than the healthy normal population. This project will improve heart health because it will address how newly-recognised proteins, called S100 proteins, mediate pathogenesis and how they are regulated in cells by various therapeutic drugs. We developed a potential diagnostic test that distinguishes patients with angina from those with arthritis and this could be useful in improving diagnosis and following treatment of patients with cardiovascular disease or arthritis. We find that some anti-inflammatory drugs enhance S100 gene expression whereas our preliminary data indicates that some cholesterol-lowering drugs (statins) reduce it. Results of treating patients with arthritis with statins will add to understanding of why cholesterol-lowering drugs commonly used in management of CVD patients may be effective in treating symptoms in arthritis sufferers and could contribute to changes in clinical management of these patients.Read moreRead less
This project will characterise the biological and functional properties of a novel human pro-inflammatory S100 protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells. These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location makes them prime targets to trigger vascular and inflamma ....This project will characterise the biological and functional properties of a novel human pro-inflammatory S100 protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells. These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location makes them prime targets to trigger vascular and inflammatory events. They are known to be important in allergy and infection and have a proposed role in chronic inflammatory processes. Although the mechanisms of mast cell activation contributing to acute responses in allergic reactions are well accepted, ways in which they are activated in asthma and other chronic inflammatory disease are virtually unknown. We will use lung biopsies from patients with asthma to detect patterns of expression of the protein and determine its effects on lung mast cells. A murine model will be used to define the characteristics of inflammation induced by the S100 protein and the role of mast cells in this process. Structural studies will define the parts of the protein necessary for mast cell activation. We will attempt to identify its receptor on mast cells to enable future studies to define how the protein triggers the cells to produce mediators such as histamine and those causing blood vessel changes. This knowledge could lead to design of novel drugs that could regulate this process. Results from this project will provide new knowledge of chronic inflammatory processes and could result in designing novel strategies to regulate these. Studies are relevant to infectious diseases and many other conditions with a chronic inflammatory basis, including asthma, rheumatoid arthritis, cardiovascular disease, cystic fibrosis and infection.Read moreRead less
Modelling Traumatic Brain Injury Using Neuropsychological, Neurosurgical, Neurochemical, And Neuroradiological Measures
Funder
National Health and Medical Research Council
Funding Amount
$403,370.00
Summary
Post mortem and brain imaging studies of patients who have had a traumatic brain injury (TBI) indicate that they sustain both focal damage and widespread diffuse damage. This diffuse damage is more difficult to detect but has been found to occur even after mild injuries and in the absence of focal brain damage. Moreover, diffuse damage is thought to contribute both to changes in a patient's level of consciousness at the time of injury and to the long-term problems experienced by patients after a ....Post mortem and brain imaging studies of patients who have had a traumatic brain injury (TBI) indicate that they sustain both focal damage and widespread diffuse damage. This diffuse damage is more difficult to detect but has been found to occur even after mild injuries and in the absence of focal brain damage. Moreover, diffuse damage is thought to contribute both to changes in a patient's level of consciousness at the time of injury and to the long-term problems experienced by patients after a TBI, suggesting that diffuse damage may provide a valuable index of the amount of brain damage that has been sustained as a result of an injury. While clinicians presently assess many cognitive abilities, they do not target the cognitive problems that are thought to arise from diffuse damage. This is largely due to an absence of validated measures and a limited understanding of the effects of diffuse damage on cognitive functioning. Consequently, we do not have a clear understanding of the extent to which diffuse damage contributes to patient outcome after a TBI. The present study is designed to provide a model of the effects of TBI that will include neuropsychological, neurosurgical, neurochemical and neuroradiological variables. The cognitive effects of diffuse damage will be assessed and related to neurochemical and brain imaging indices of diffuse damage in order to examine the relationship between brain structure and function. This study will improve our understanding of the effects of diffuse damage on cognitive functioning and will lead to the development of measures that can be used to assess the consequences of diffuse damage. In doing so, this study will improve the accuracy with which we are able to diagnose the cognitive problems of patients who have suffered a TBI. This will, in turn, reduce the public health, insurance and litigation costs associated with this type of injury.Read moreRead less