Macrophage Uncoupling Protein-2 Regulation And Expression In Inflammatory Joint Disease And Hyperoxic Lung Damage
Funder
National Health and Medical Research Council
Funding Amount
$270,013.00
Summary
Oxygen radicals (OR) are made by white blood cells (WBC) when they protect against microbes and cancer cells. However, excessive production also damages normal tissue, for example in lungs that receive too much oxygen (hyperoxic lung damage) or in inflamed joints. One type of WBC, the macrophage has a protein named UCP2, that limit the amount of OR formation. This project aims to find out how macrophages activate UCP2 and whether they do so in inflammatory arthritis and hyperoxic lung damage.
Novel Strategies To Boost Tristetraprolin Function: A Critical Anti-inflammatory Protein In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$547,216.00
Summary
Asthma is a chronic disorder where airways are remodelled, resulting in poor lung function. Airway remodelling is a consequence of long-term inflammation. As current treatments halt some, but not all, aspects of airway remodelling, new therapeutic approaches are urgently required. In this grant, our aim is to devise novel strategies to boost the function of a critical anti-inflammatory protein - TTP - to reduce inflammation in asthma.
Elucidating The Role Of Mast Cell Tryptases In Chronic Obstructive Pulmonary Disease And Crohn's Disease
Funder
National Health and Medical Research Council
Funding Amount
$620,716.00
Summary
Smoking leads to inflammation that causes emphysema and inflammation in the lung and gut, which are major health problems. Once induced, there is a progressive decline in health and there are no effective treatments. Particular proteins and small genes have been discovered that control inflammation in these diseases. We may be able to control these proteins/genes and stop the progression of emphysema and gut inflammation. This project may lead to a completely new way of preventing and treating t ....Smoking leads to inflammation that causes emphysema and inflammation in the lung and gut, which are major health problems. Once induced, there is a progressive decline in health and there are no effective treatments. Particular proteins and small genes have been discovered that control inflammation in these diseases. We may be able to control these proteins/genes and stop the progression of emphysema and gut inflammation. This project may lead to a completely new way of preventing and treating these diseases.Read moreRead less
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
Identifying New Therapeutic Targets For Preventing The Induction And Progression Of COPD
Funder
National Health and Medical Research Council
Funding Amount
$649,314.00
Summary
Smoking leads to lung inflammation that causes emphysema, which is a major health problem in Australia. Once induced there is a progressive decline in health, which continues even after stopping smoking. There are no treatments that halt this decline. Recently small genes have been discovered that control inflammation. We may be able to control these small genes and stop the induction and progression of emphysema. This project may lead to a completely new way of preventing and treating emphysema ....Smoking leads to lung inflammation that causes emphysema, which is a major health problem in Australia. Once induced there is a progressive decline in health, which continues even after stopping smoking. There are no treatments that halt this decline. Recently small genes have been discovered that control inflammation. We may be able to control these small genes and stop the induction and progression of emphysema. This project may lead to a completely new way of preventing and treating emphysema.Read moreRead less
G-CSF: A Pathogenic Effector In Chronic Obstructive Pulmonary Disease And Its Comorbidities
Funder
National Health and Medical Research Council
Funding Amount
$1,241,551.00
Summary
Chronic Obstructive Pulmonary Disease (COPD) is an incurable lung disease that is a huge global health burden, and new therapies are urgently needed. We have recently discovered a possible cause of COPD. This single factor also appears to drive other associated medical problems that are the biggest contributors to patient deterioration. Using advanced genetics, biochemistry and molecular methods we are searching for ways to turn our discovery into effective treatments for this fatal disease.
Mannitol In The Assessment Of Bronchial Responsiveness In Airway Disease
Funder
National Health and Medical Research Council
Funding Amount
$365,250.00
Summary
The airways of people with asthma respond by narrowing too easily and too much to a wide range of stimuli. The tests most commonly used to measure airway responsiveness in asthma are the pharmacological agents methacholine and histamine. When inhaled, they act directly on bronchial muscle causing it to contract and hence the airways to narrow. We have developed a non-pharmacological test using a dry powder of a sugar - mannitol. When inhaled, mannitol causes narrowing of the airways in asthmatic ....The airways of people with asthma respond by narrowing too easily and too much to a wide range of stimuli. The tests most commonly used to measure airway responsiveness in asthma are the pharmacological agents methacholine and histamine. When inhaled, they act directly on bronchial muscle causing it to contract and hence the airways to narrow. We have developed a non-pharmacological test using a dry powder of a sugar - mannitol. When inhaled, mannitol causes narrowing of the airways in asthmatics but little or no effect in healthy subjects. Many asthmatics respond to mannitol even when they have few symptoms of asthma. Mannitol causes the airways to narrow 'indirectly' by causing the release of substances from inflammatory cells in the airways (e.g. histamine, leukotrienes and prostaglandins) that cause the muscle to contract. After the inflammation has cleared, either by treatment with inhaled steroids or spontaneously, the response to mannitol is close to healthy subjects. Thus the response to mannitol depends on the presence of inflammation and loss of responsiveness means resolution of inflammation. The significance of this is that the mannitol test may be used as an 'inflammometer'. It would be important if airway responsiveness to mannitol could be used to identify individuals with airway diseases other than asthma, (chronic bronchitis, and chronic obstructive lung disease) who could benefit from treatment with inhaled steroids. This would be significant as there is currently no test to identify those individuals and there are unwanted effects from using steroids. Further, it may be possible to use mannitol to identify individuals with other inflammatory diseases who may be at risk of developing asthma. Some people with asthma, chronic bronchitis and chronic obstructive lung disease have increased levels of oxidative stress. We wish to identify those people and to measure change after treatment with steroids.Read moreRead less
The Anti-inflammatory Role Of Collagen IV In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$317,076.00
Summary
We have discovered that a protein, tumstatin, is missing from the lungs of people with asthma. We now have exciting data showing, for the first time, that tumstatin can stop inflammation. If tumstatin is part of the system that normally limits inflammation in the lungs its absence in asthma may be critical. In this grant we will discover how tumstatin works to block inflammation and why it is absent in asthma. Our studies will provide vital information about the role of tumstatin in the airways.