Australia has one of the highest asthma rates in the world. In this project we will study how natural regulatory T cells suppress asthma in a mouse model. We will determine where and when interactions between regulatory T cells and allergic T cells occur, and define the mechanisms used by regulatory cells to mediate their suppressive effects. Our findings will aid in understanding why asthma develops and how it may be controlled by the immune system itself.
Asthma is a significant burden to the health care system and to individual sufferers. Currently we can treat asthma with corticosteroids to reduce inflammation in the lung but the side effects of these medications, particularly in children, make them less than ideal treatments. In order to design a more specific treatment for asthma, which would only target the inflammatory cells which are involved in the lung, we need to understand how these cells behave and what initiates the cascade of events ....Asthma is a significant burden to the health care system and to individual sufferers. Currently we can treat asthma with corticosteroids to reduce inflammation in the lung but the side effects of these medications, particularly in children, make them less than ideal treatments. In order to design a more specific treatment for asthma, which would only target the inflammatory cells which are involved in the lung, we need to understand how these cells behave and what initiates the cascade of events in the lung. This project is designed to investigate how chemical mediators, cytokines, are produced by various cells in the lung and how they induce lung cells to make structural changes to the lung tissue and increase the inflammation. The source and specific types of cytokines released are being investigated to provide important information regarding the disease process of asthma. From this new knowledge, design of specific new treatments, with fewer unwanted side-effects, should be possible.Read moreRead less
Airway Inflammation In Asthma And Chronic Obstructive Pulmonary Disease
Funder
National Health and Medical Research Council
Funding Amount
$390,509.00
Summary
In chronic diseases of the airway such as asthma and airway narrowing due to cigarette smoking - chronic obstructive pulmonary disease (COPD), the airways show inflammation (increased numbers of cells and their products) and remodelling (increased thickness and scarring) which persist for many years, possibly indefinitely. The exact mechanisms by which inflammation persists in the airway wall in asthma and COPD are unknown. We and others have shown that greater numbers of memory T-lymphocytes (T ....In chronic diseases of the airway such as asthma and airway narrowing due to cigarette smoking - chronic obstructive pulmonary disease (COPD), the airways show inflammation (increased numbers of cells and their products) and remodelling (increased thickness and scarring) which persist for many years, possibly indefinitely. The exact mechanisms by which inflammation persists in the airway wall in asthma and COPD are unknown. We and others have shown that greater numbers of memory T-lymphocytes (T-cells) are present in the airway wall in asthma and COPD. T-cells orchestrate the processes involved in inflammation. We have hypothesised that the persistence of airway inflammation in asthma and COPD results from the proliferation of memory T-cells within the airway wall. Unlike na ve T-cells, memory T-cells have previously been stimulated and can easily be activated to proliferate and promote inflammation by other cells which are fixed in the airway. Data from our current work examining this process suggests that, although cells fixed in the airway such as fibroblasts and macrophages are activated in asthma and COPD and may activate T-cells, they do not seem to be causing T-cell proliferation. We now wish to extend these studies by determinimg if memory T- lymphocytes are proliferating in the airway wall within aggregations of lymphoid cells which act like lymph nodes and promote T-cell growth. To do this we will compare the number of these aggregations and the types of T-cells they contain in mild and severe cases of asthma and COPD with those in normal subjects. This work will provide new knowledge to help understand the mechanisms for the persistance of airway inflammation in asthma and COPD and may thereby also provide a focus for effective treatments of these condition.Read moreRead less
Asthma Prevention And Treatment Using UVB Radiation-induced Immunomodulation
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
The prevalence of asthma is increasing despite the adoption of modern expensive drugs. Our studies suggest that exposure of skin to an erythemal dose of the wavelengths of UVB radiation found in sunlight can suppress responses to allergens encountered in the airways. We are requesting support to study the mechanisms in mice by which exposure to UVB radiation on their shaved backs can reduce inflammation in the airway mucosa upon allergen exposure. Whole body immunomodulatory effects of UVB radia ....The prevalence of asthma is increasing despite the adoption of modern expensive drugs. Our studies suggest that exposure of skin to an erythemal dose of the wavelengths of UVB radiation found in sunlight can suppress responses to allergens encountered in the airways. We are requesting support to study the mechanisms in mice by which exposure to UVB radiation on their shaved backs can reduce inflammation in the airway mucosa upon allergen exposure. Whole body immunomodulatory effects of UVB radiation have been previously described but have not been scientifically linked with asthma development. This is a very new and novel research area which supports century-old anecdotal reports that holidays at beach and mountain resorts associated with increased UVB exposure are beneficial in asthma treatment. This is a proof of principle study. If we can confirm that UVB is immunomodulatory and better understand the mechanisms by which UVB suppresses inflammation in the airways, we will investigate the potential of non-carcinogenic, UVB-induced, skin-derived intermediary molecules to have the same regulatory effects.Read moreRead less
Mast Cells - Bystanders Or Instigators Of Airway Remodelling In Asthma?
Funder
National Health and Medical Research Council
Funding Amount
$623,764.00
Summary
Current asthma treatments have little effect on changes to the breathing tubes in our lungs. The tubes are thickened and stiffer, with more muscle, blood vessels, matrix and mucus. We propose that a particular inflammatory cell, called a mast cell, causes these changes to the breathing tubes and we will find out how it does that. Thus this project will establish why and how the changes to the breathing tubes happen in asthma and reveal how best to target and reverse-prevent them in the future.
Airway Smooth Muscle - Mast Cell Cross Talk In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$527,250.00
Summary
In Australia 1 in 4 children and 1 in 10 adults are asthmatic and so asthma is a significant burden to our community and our healthcare system. Currently we treat asthma with corticosteroids to reduce airway inflammation because, without them, chronic inflammation leads to thickened airways with increased amounts of smooth muscle that contracts too much and too easily. However, corticosteroids may have side effects , particularly in children. In order to design safer more specific treatments for ....In Australia 1 in 4 children and 1 in 10 adults are asthmatic and so asthma is a significant burden to our community and our healthcare system. Currently we treat asthma with corticosteroids to reduce airway inflammation because, without them, chronic inflammation leads to thickened airways with increased amounts of smooth muscle that contracts too much and too easily. However, corticosteroids may have side effects , particularly in children. In order to design safer more specific treatments for asthma, we need to know more about the pattern of inflammation that is specific for asthma and what chemical signals cause it. Then we will be able to target it more specifically. Recent research has demonstrated that in asthma, but not in bronchitis or in healthy people, inflammatory cells called mast cells are found in increased numbers down in the smooth muscle layer of the airways. Mast cells are key cells in all allergic reactions. In the airways they release mediators that contract the airways, induce mucous secretion and promote further inflammation. We think the effects airway smooth muscle cells and mast cells have on each other are central factors in causing the physical changes to the airways of asthmatics. We will identify what chemical messages released by the smooth muscle attract mast cells to it and once they are there, what the mast cells stick to on the smooth muscle. Then we will investigate how the two cell types interact with each other and affect each other. We will focus on how the functions of the smooth muscle cells are affected, especially those that would promote further inflammation and lead to increased amounts of more sensitive, more contractile smooth muscle. We will try to prevent each of the steps we identify with drugs that have very specific actions. This additional information may lead to the design of novel treatments for asthma that have fewer side effects.Read moreRead less
The Role Of The Hedgehog Signaling Pathway In Asbestos Associated Malignant Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$563,554.00
Summary
Mesothelioma is a aggressive asbestos related cancer mainly of the lung with no effective treatment. Evidence is pointing to the reactivation and aberrant expression of developmental signalling pathways such as the hedgehog signalling pathway as critical to the pathogenesis of certain types of cancer. This study will determine if mesothelioma is regulated by signalling through the hedgehog pathway and by blocking this pathway we will attempt to inhibit tumour growth.
Airway Epithelial IAPs And Their Interaction With Zn Ions
Funder
National Health and Medical Research Council
Funding Amount
$260,779.00
Summary
The air we breathe contains a variety of harmful substances. Damage to the lining involves death of the ciliated cells that line the airways. We have shown that zinc protects these cells from premature death. This application focuses on a family of proteins called IAPs which bind zinc and regulate cell death in other tissues. This project focusses on how the IAPs and Zn may act together to mainitain healthy airways and how abnormalities of these may occur in people with asthma.
The Mechanisms Of Infection Of Bronchial Epithelial Cells By Human And Avian Influenza Viruses In Chronic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$395,559.00
Summary
Influenza is an important infection that causes disease every year in the Australian population. People with lung disease are at particular risk to its effects. The ability of the virus to grow in birds and change its appearance to our immune system allows this virus to cause severe disease every year. We will examine the immune response to this virus in human cells, comparing this response to human and bird strains of the virus and see why subjects with lung disease are more susceptible.
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