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.
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.
Switching Tristetraprolin On To Turn Off Inflammation In COPD
Funder
National Health and Medical Research Council
Funding Amount
$525,390.00
Summary
Inflammation drives the pathogenesis of chronic obstructive pulmonary disease (COPD). We have developed a novel anti-inflammatory strategy to treat this currently untreatable disease. Our innovation is to use activators of protein phosphatase 2A to switch the molecule tristetraprolin (TTP) on and repress inflammation in COPD. Switching TTP on to turn off inflammation in COPD has proven potential to prevent irreversible damage and halt the progression of COPD.
The Role Of The Alveolar Macrophage In The Regulation Of Inflammation And Matrix Destruction In COPD
Funder
National Health and Medical Research Council
Funding Amount
$397,420.00
Summary
Chronic obstructive pulmonary disease (COPD) is a major public health problem world-wide. COPD is a common disease and a leading cause of morbidity and mortality. The prevalence, morbidity and mortality of COPD are increasing in many westernized countries. Chronic cigarette smoking is the main cause of COPD, and the demographics of COPD reflect the demographics of cigarette smoking. Globally, 47% of men and 12% of women smoke, but only 15% of smokers will develop COPD. Cells within the lung call ....Chronic obstructive pulmonary disease (COPD) is a major public health problem world-wide. COPD is a common disease and a leading cause of morbidity and mortality. The prevalence, morbidity and mortality of COPD are increasing in many westernized countries. Chronic cigarette smoking is the main cause of COPD, and the demographics of COPD reflect the demographics of cigarette smoking. Globally, 47% of men and 12% of women smoke, but only 15% of smokers will develop COPD. Cells within the lung called alveolar macrophage produce substances called proteins called cytokines and matrix metalloproteinases (MMPs) which may be important in the development of emphysema or COPD. In COPD, these patients have an inflammatory and destructive process in their lungs, which leads to a progressive loss of breathing capacity, and ultimately death. There have been significant improvements in the treatment of asthma over the last 30 years. Effective new drugs such as selective and long-acting bronchodilators, more effective inhaled corticosteroids, and improved delivery systems have been introduced. Arguably inhaled steroids may be the single most important treatment in preventing the symptoms and exacerbations of asthma and although useful in asthma, the benefits of inhaled steroids in COPD has not yet been established, but inhaled steroids are still used in the treatment of COPD despite the paucity of evidence for its usefulness in patients with COPD. This treatment is expensive and may also produce side-effects. We would like to investigate the effect of inhaled steroids on several inflammatory and destructive processes in patients with COPD. These studies will form the basis of a more rational approach in the management of COPD. Improved understanding of the molecular mechanisms that underlie COPD could lead to improved treatments for this disease which is set to be the third most important cause of death in 2010.Read moreRead less
Understanding Corticosteroid-sensitive And -insensitive Pathways In Airway Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$299,270.00
Summary
Asthma and chronic obstructive pulmonary disease (COPD) are chronic disorders of the airways affecting millions of people worldwide. Airways become remodelled, or thickened, resulting in airway obstruction and decline in lung function. Approximately 400 asthmatics and 6000 COPD sufferers die in Australia each year. Worryingly, COPD is currently the fourth highest cause of death in Australia and this number is predicted to increase in the future. Unfortunately, the drugs currently available for c ....Asthma and chronic obstructive pulmonary disease (COPD) are chronic disorders of the airways affecting millions of people worldwide. Airways become remodelled, or thickened, resulting in airway obstruction and decline in lung function. Approximately 400 asthmatics and 6000 COPD sufferers die in Australia each year. Worryingly, COPD is currently the fourth highest cause of death in Australia and this number is predicted to increase in the future. Unfortunately, the drugs currently available for combating these diseases have limited success. We need to understand how to control airway remodelling to be able to improve treatments for asthma and COPD. But first we require a greater understanding of the molecular mechanism-s underlying the development of airway remodelling. With this proposal we will increase our knowledge of the mechanistic basis of asthma and COPD and may elucidate novel therapeutic targets for future pharmacological intervention.Read moreRead less
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.
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