Molecular Characterisation Of TRAIL-regulated Signal Transduction Pathways And Their Role In The Development, Persistence, And Exacerbation Of Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$637,035.00
Summary
Molecules that promote the development, persistence, and exacerbation of asthma are only poorly defined. We have discovered a novel signalling pathway that is activated in the airway wall during asthma. Blocking a molecule that activates this pathway ameliorated asthma in mice. We now want to identify all the important components of this pathway and therapeutically modulate them to prevent the development, persistence, and exacerbation of asthma.
Asthma causes a unique type of inflammation in the airways. Until recently, the cell responsible for this inflammation was thought to be the eosinophil. Eosinophils are evaluated in sputum samples from the airways and are commonly reported in increased levels from people with asthma. Recent work has identified that some people have symptoms of asthma but their eosinophil levels remain normal. Those with non-eosinophilic asthmatics may account for up to 50% of all asthma reported. Our study will ....Asthma causes a unique type of inflammation in the airways. Until recently, the cell responsible for this inflammation was thought to be the eosinophil. Eosinophils are evaluated in sputum samples from the airways and are commonly reported in increased levels from people with asthma. Recent work has identified that some people have symptoms of asthma but their eosinophil levels remain normal. Those with non-eosinophilic asthmatics may account for up to 50% of all asthma reported. Our study will investigate the cells present in the sputum of people that have non-eosinophilic asthma. It has been speculated that neutrophils (another cell causing inflammation in the lungs) may be responsible. Neutrophils are known to cause inflammation and release many chemical mediators, which are capable of destroying lung tissue. We will focus on the neutrophil and the chemicals that cause neutrophils to move into the lungs and then destroy tissue. By comparing the levels of neutrophils and its mediators between the eosinophilic and non-eosinophilic asthma populations it may be possible to understand the mechanism behind non-eosinophilic asthma. Current asthma treatments-preventers focus essentially on controlling the inflammation caused by eosinophils. By understanding what is causing the inflammation in people without eosinophils in their sputum, we can begin to investigate and design new treatments. One possible treatment is the use of macrolide antibiotics. These medicines have been shown to be useful in reducing inflammation in other chronic inflammatory diseases. We plan to investigate the usefulness of a macrolide antibiotic (erythromycin) in reducing inflammation in non-eosinophilic asthma by a randomised-controlled trial. Armed with more information about non-eosinophilic asthma we will be able to more effectively diagnose and treat this group in the community.Read moreRead less
Novel Candidate Genes, Lung Function And Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
We propose to study airway remodelling (structural changes to the airway) and in asthma using human samples and rodent models of asthma. We are particularly interested in investigating the role of trefoil peptide 2 and relaxin, two genes identified as determining lung function. To do this we need to understand the mechanisms of airway remodelling and its impact on disease severity in the patient. A strength of this study is availability of samples from a large study of human asthma.
Distribution Of Monodisperse Aerosols Inhaled By Children For Determination Of Optimal Therapeutic Inhaler Formulations
Funder
National Health and Medical Research Council
Funding Amount
$326,000.00
Summary
Inhalers are the primary form of treatment for asthma, allowing the delivery of lower doses of medication directly to the lungs. Consistent daily use of these inhalers is often necessary to effectively control the symptoms of asthma. Inhalers are now increasingly used to treat infants with lung problems. Many of these inhalers are not designed for use by such young children, who may be unable to perform the breathing techniques necessary for effective use of these inhalers. Not all the drug inha ....Inhalers are the primary form of treatment for asthma, allowing the delivery of lower doses of medication directly to the lungs. Consistent daily use of these inhalers is often necessary to effectively control the symptoms of asthma. Inhalers are now increasingly used to treat infants with lung problems. Many of these inhalers are not designed for use by such young children, who may be unable to perform the breathing techniques necessary for effective use of these inhalers. Not all the drug inhaled by patients will end up in the lungs where it is needed; a large proportion is left in the mouth, throat and stomach. Our earlier studies have shown that there is a large amount of variability in the amount of drug received by children using inhalers. We intend to assess the important factors involved in improving the efficiency of inhaler therapy for children, such as the size of the inhaled particles and the breathing pattern of the child. The results obtained from this study will enable us to determine the best method of delivering these drugs to children so that they only receive the lowest effective dose for treatment of the symptoms of asthma while minimising unwanted effects.Read moreRead less
Airway Inflammation In Allergic Aspergillosis: Characterisation, Immunologic Mechanisms And Treatment.
Funder
National Health and Medical Research Council
Funding Amount
$242,562.00
Summary
Aspergillus fumigatus is a fungus that commonly occurs in our community. In some people with asthma, this fungus causes the asthma to become severe and chronic. It may also be associated with a severe form of lung destruction called bronchiectasis. There is little known about the chemicals produced by the body which contribute to inflammation in this condition. Similarly, it is not known why only some people with asthma develop an allergic disease to this fungus. In this project we will examine ....Aspergillus fumigatus is a fungus that commonly occurs in our community. In some people with asthma, this fungus causes the asthma to become severe and chronic. It may also be associated with a severe form of lung destruction called bronchiectasis. There is little known about the chemicals produced by the body which contribute to inflammation in this condition. Similarly, it is not known why only some people with asthma develop an allergic disease to this fungus. In this project we will examine 2 important inflammation chemicals (called cytokines) to examine what their role is in aspergillus associated allergy. We will also examine 2 genetic markers to establish whether these predispose to people developing allergy to aspergillus. The treatment of aspergillus lung disease is also problematic. In this project we will examine whether a new medication called itraconazole is effective in removing this fungus from the airway and improving asthma.Read moreRead less
Macrophages, Sugars And Innate Immunity In Chronic Lung Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$413,150.00
Summary
This project is about a new idea to treat severe asthma, chronic obstructive lung disease (COPD) and sudden worsening of these diseases (exacerbations). Asthma and COPD are very common. Asthma afflicts approximately 10 % of all Australians and kills approximately 700 annually. COPD will be the third most common cause of death worldwide by 2010 (WHO) and costs more that $ AUS 10 Billion annually. The highest risk of death and greatest costs are associated with severe asthma and exacerbations. Our ....This project is about a new idea to treat severe asthma, chronic obstructive lung disease (COPD) and sudden worsening of these diseases (exacerbations). Asthma and COPD are very common. Asthma afflicts approximately 10 % of all Australians and kills approximately 700 annually. COPD will be the third most common cause of death worldwide by 2010 (WHO) and costs more that $ AUS 10 Billion annually. The highest risk of death and greatest costs are associated with severe asthma and exacerbations. Our idea, which is based on extensive animal data, is that these diseases can be treated by blocking the activity of proteins that allow a cell called the lung macrophage to grow, become activated, proliferate and survive. These proteins are called CSF-1 and GM-CSF and they belong to a larger class of proteins called colony stimulating factors (CSFs) Macrophages are important because they can rapidly respond to bacteria, viruses and fungi that can infect the lungs of asthma and COPD patients. Infections cause exacerbations. Normally, macrophages release a number of molecules called mediators that rouse a strong defensive reaction- a process called innate immunity. For example macrophages signal for a cell type called the neutrophil, which is a very efficient bacteria killer, to flood into the lung. However, these same cells can cause serious lung damage if the response is too strong or persistent. Macrophages and neutrophils need CSFs to work properly so blocking CSFs prevents lung damage. Although we now already know that blocking CSFs can prevent and reverse lung inflammation we still need to know a great deal more in order to know if this approach will be useful to treat people in the future. Our project is therefore all about understanding the fine detail of how CSFs can damage the lung. The importance of the project is that our work may lead to entirely new, and much more effective, treatments for people suffering from asthma and COPD.Read moreRead less
Outcome Of Childhood Asthma In Adult Life And The Interaction With COPD
Funder
National Health and Medical Research Council
Funding Amount
$503,549.00
Summary
The Melbourne Study of Childhood Asthma (MESCA) is the longest, most comprehensive follow-up study of childhood asthma. The members were recruited in 1964 at the age of 7 and they have been reviewed at ages 10, 14, 21, 28, 35 and 42 years of age with a retention rate of 87% of survivors at the most recent follow-up. To date, the MESCA study has provided comprehensive data on the outcome of childhood asthma through to their adult years and has been particularly influential in establishing approac ....The Melbourne Study of Childhood Asthma (MESCA) is the longest, most comprehensive follow-up study of childhood asthma. The members were recruited in 1964 at the age of 7 and they have been reviewed at ages 10, 14, 21, 28, 35 and 42 years of age with a retention rate of 87% of survivors at the most recent follow-up. To date, the MESCA study has provided comprehensive data on the outcome of childhood asthma through to their adult years and has been particularly influential in establishing approaches to treatment of paediatric asthma nationally and internationally. The results of the study have been published widely over the years and cited extensively. The members of this cohort turn 50 in 2007 and will be invited to participate in a further review to reassess their clinical outcome to examine the relationship between long standing asthma and the development of COPD. Those members of the cohort who have had asthma persisting through their adult years have a degree of fixed obstruction on their tests of lung function and are potentially at risk of developing COPD. Some are at increased risk as approximately 30% of the members are regular smokers. In this review, at age 59 years, there is an excellent opportunity to examine the interaction of asthma and COPD and to compare the inflammatory processes between those who have continuing asthma, those whose asthma has resolved and in each group examine the effect of smoking. We will also look at a numbers of genetic markers associated with COPD to identify those who are more susceptible to the development of COPD. A second area of interest is the components of the immune system that influence asthma.. In an earlier study we identified one component of the immune system, known as the T cell system, that had returned to normal in those whose asthma had resolved. In this review, we plan to examine the T cell system in detail to understand what mechanisms may be responsible for resolution of childhood asthma.Read moreRead less
The Effect Of Chronic Maternal Asthma And Acute Exacerbations On Placental Function And Fetal Development
Funder
National Health and Medical Research Council
Funding Amount
$224,623.00
Summary
Maternal asthma is the most common disease to complicate pregnancies in Australia. The data we have collected so far suggests that asthma represents a physiological maternal stress during pregnancy that influences placental function and fetal development. The purpose of this grant is to continue to determine what changes occur in the presence of maternal asthma that alter fetal growth. The findings of this work will be applicable to any psycho-social or physiological stressor during pregnancy.