Understanding The Mechanisms Of Steroid Resistant Inflammatory Pathways In Mouse Models Of Asthma: Potential New Treatment Approaches
Funder
National Health and Medical Research Council
Funding Amount
$523,694.00
Summary
Steroids are used to treat asthma but some patients are resistant to therapy, and there is no effective treatment. Such patients suffer greater morbidity and mortality, and the heath care cost for clinical management is a significant economic burden. In this project we will obtain a better understanding of the mechanisms that regulate steroid-resistant components of disease, which control inflammation and narrowing of the airway. These studies will be central to the development of new therapies.
Phenotypic And Functional Characterisation Of CD4 T Helper 22 Cells And Their Role In The Regulation Of Chronic Allergic Disease Of The Lung And Skin
Funder
National Health and Medical Research Council
Funding Amount
$714,061.00
Summary
Allergic inflammatory diseases such as asthma and allergic dermatitis are major health problems in our community that lead to poor quality of life. These diseases are induced by activation of immune cells known as T helper (Th) lymphocytes. Recently Th22 cells have been identified in patients with allergic diseases. In this study we will, for the first time, characterise these cells and determine their role in the processes that lead to chronic inflammation in asthma and allergic dermatitis.
Characterising The Pro-inflammatory Role Of IL-36γ/IL-36R In Pathogen-induced Exacerbations Of Asthma And COPD
Funder
National Health and Medical Research Council
Funding Amount
$738,768.00
Summary
Lung infections cause exacerbations in patients with asthma and COPD and these are difficult to treat and can be life-threatening. We have discovered that the cytokine pathway, IL-36?/IL-36R, is linked to the host response to bacterial and viral infections that induce exacerbations in these patients. Our studies will provide new insight into the role IL-36?/IL-36R in infection, disease exacerbation and determine the therapeutic benefit of blocking this pathway.
Mast Cell Proteases Suppress Respiratory Viral Infections And Alleric Inflammation Of The Airways
Funder
National Health and Medical Research Council
Funding Amount
$665,532.00
Summary
Severe RSV infection and asthma accounts for poor quality of life in our community and current treatments have limited effects. Although the factors regulating these disorders are poorly understood, mast cells (MCs) may play important roles. We have shown MC protease-6 protects against viral infection. Here we will identify how MC and their factors are involved in the control of severe respiratory infections and allergic disease of the lung, and identify potential new ways to treat these conditi ....Severe RSV infection and asthma accounts for poor quality of life in our community and current treatments have limited effects. Although the factors regulating these disorders are poorly understood, mast cells (MCs) may play important roles. We have shown MC protease-6 protects against viral infection. Here we will identify how MC and their factors are involved in the control of severe respiratory infections and allergic disease of the lung, and identify potential new ways to treat these conditions.Read moreRead less
Targeting MicroRNA (miRNA) As A Unified Therapeutic Approach To The Treatment Of Asthma And Allergic Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$675,030.00
Summary
Approximately 30% of our community suffers from allergic inflammation (asthma/rhinitis/dermatitis) that results in poor quality of life. The factors regulating these disorders are poorly understood and current treatments only target the symptoms and not the cause of disease. MicroRNA control gene expression and are emerging as potential regulators of inflammation. This project will identify the role of microRNA in the regulation of allergic diseases and their potential as new therapeutic targets ....Approximately 30% of our community suffers from allergic inflammation (asthma/rhinitis/dermatitis) that results in poor quality of life. The factors regulating these disorders are poorly understood and current treatments only target the symptoms and not the cause of disease. MicroRNA control gene expression and are emerging as potential regulators of inflammation. This project will identify the role of microRNA in the regulation of allergic diseases and their potential as new therapeutic targets.Read moreRead less
Molecular Mechanisms Of Wasting In Experimental COPD
Funder
National Health and Medical Research Council
Funding Amount
$389,521.00
Summary
Chronic obstructive pulmonary disease (COPD) is a major global health problem and has been predicted to become the third largest cause of death in the world by 2020. Cigarette smoking is the major cause of COPD and accounts for more than 95% of cases in industrialized countries. Currently no therapies exist to halt the inevitable progression of the disease. To date most of the research has focused on the aspects of this disease which result in destruction of the lung however it is becoming incre ....Chronic obstructive pulmonary disease (COPD) is a major global health problem and has been predicted to become the third largest cause of death in the world by 2020. Cigarette smoking is the major cause of COPD and accounts for more than 95% of cases in industrialized countries. Currently no therapies exist to halt the inevitable progression of the disease. To date most of the research has focused on the aspects of this disease which result in destruction of the lung however it is becoming increasingly evident that COPD is a disease of multiple organs. Until recently it had been widely believed that the profound loss of exercise tolerance observed in COPD patients was due to impaired gas exchange secondary to lung structural damage. Loss of lean body mass (muscle) is now recognised as a major co-morbidity of COPD and a direct cause of functional impairment with patients suffering marked deteriorations in quality of life, increased mortality, breathlessness and decreased exercise tolerance. Skeletal muscle wasting is a powerful predictor of mortality in COPD, independent of the lung function impairment. Despite the clinical seriousness of muscle wasting and suggestive evidence that it may be reversible, little is known about the pathogenic mechanisms. Therefore the goal of this project is to use experimental models of COPD to identify the molecular basis of wasting, in order to restore skeletal muscle homeostasis. The insights gained from this research proposal may lead to the identification of potentially novel targets for the prevention and reversal of the debilitating and life threatening effects of skeletal muscle wasting in COPD. For the COPD patient this has the potential to increase quality of life, functional ability and life expectancy.Read moreRead less
Fetal Growth Restriction, Low Birth Weight And The Development Of Asthma
Funder
National Health and Medical Research Council
Funding Amount
$397,003.00
Summary
Asthma is a common disease in Australia that causes breathing difficulties. Studies have shown that restricted growth in the womb may be linked to developing asthma in childhood and adulthood. The reason for this isn't clear but we believe that restricted growth may alter the normal development of the baby's airway and lungs. Changes to the normal structure of the lungs leads to a higher risk of developing asthma.
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
Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown cause which is unresponsive to current therapy. This study builds on recent work by this group highlighting the importance of a cell signalling molecule called STAT3 in the development of this disease. In particular, two cell types that utilise STAT3 signalling, epithelial cells and B cells, will be examined to see if blocking their STAT3 responses could be a novel therapeutic approach.
Hydrostatic Pressure Distributions In Peri-pharyngeal Tissues : Impact On Upper Airway Patency
Funder
National Health and Medical Research Council
Funding Amount
$508,935.00
Summary
The obstructive sleep apnoea hypopnoea syndrome (OSAHS) refers to a condition in which throat blockage occurs during sleep leading to breathing difficulties, including cessation of breathing for short periods of time. OSAHS affects both men and women but is amongst the commonest of chronic disorders of adult males, occurring in ~4% of men over the age of 45 years. In the proposed studies we will develop a computer model of the function of the throat during breathing. A particular focus of our mo ....The obstructive sleep apnoea hypopnoea syndrome (OSAHS) refers to a condition in which throat blockage occurs during sleep leading to breathing difficulties, including cessation of breathing for short periods of time. OSAHS affects both men and women but is amongst the commonest of chronic disorders of adult males, occurring in ~4% of men over the age of 45 years. In the proposed studies we will develop a computer model of the function of the throat during breathing. A particular focus of our model will be the influence of the properties of the tissue that form the walls of the throat. Our goal is to construct a computer model that will be useful in identifying specific features of throat function that make people susceptble to the development of OSAHS. In this manner we hope to provide a tool that can be used to develop new approaches to the treatment and prevention of OSAHS.Read moreRead less