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Abnormal Smooth Muscle Behaviour In Asthma: Toward An In Vivo Test
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
In order to understand asthma better, and to improve our ability both to prevent and to treat the disease, we need to understand why the airways of people with asthma narrow too easily and too much. Airway hyperresponsiveness is almost certainly a downstream consequence of several different abnormalities. Airway inflammation, resulting from an allergic reaction in the airways, probably plays a major role. It is also likely that the smooth muscle in the airways contributes to airway narrowing, bu ....In order to understand asthma better, and to improve our ability both to prevent and to treat the disease, we need to understand why the airways of people with asthma narrow too easily and too much. Airway hyperresponsiveness is almost certainly a downstream consequence of several different abnormalities. Airway inflammation, resulting from an allergic reaction in the airways, probably plays a major role. It is also likely that the smooth muscle in the airways contributes to airway narrowing, but at present we have no way to measure airway behaviour in the living human. In this project we will examine the response of the airways to a deep breath, to determine if this is an indicator of smooth muscle behaviour. When the airways are narrowed, taking a deep breath stretches them and helps to overcome the narrowing. It is well known that this stretching mechanism is impaired in asthma, probably as a result of inflammatory changes to the airway wall. What is less well known is that after the airway has been stretched by a deep breath, it re-narrows, and there is new evidence that the rate of re-narrowing is increased in asthma. Based on our knowledge of how the smooth muscle behaves in the organ bath, and of the types of abnormal behaviour found in muscle from allergic and some asthmatic people, it seems likely that the rate of airway re-narrowing following a deep breath is an indicator of smooth muscle behaviour. This hypothesis has not been tested before. If we can establish that the rate of re-narrowing is an indicator of smooth muscle behaviour, we can then determine if abnormal muscle behaviour occurs in asthma, and examine the factors associated with abnormal muscle behaviour. This will improve our understanding of the basic abnormalities in asthma, and facilitate studies to see if this test can predict who is at risk from developing asthma. Evidence that smooth muscle behaviour is abnormal in asthma may suggest new directions for drug therapy.Read moreRead less
Expression And Function Of Fatty Acid Binding Proteins In Asthmatic Airway Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$226,500.00
Summary
Asthma is an inflammatory disease of the lungs that affects over 10% of all Australians. It ranges in severity from mild to life-threatening. Although a number of drugs are currently available for the treatment of asthma, there are many people whose asthma does not respond very well to treatment. We have recently identified a gene called aP2 that is important in the development of asthma. Drugs targeted against this gene may be very useful in the treatment of asthma. In this project, we aim to u ....Asthma is an inflammatory disease of the lungs that affects over 10% of all Australians. It ranges in severity from mild to life-threatening. Although a number of drugs are currently available for the treatment of asthma, there are many people whose asthma does not respond very well to treatment. We have recently identified a gene called aP2 that is important in the development of asthma. Drugs targeted against this gene may be very useful in the treatment of asthma. In this project, we aim to understand how aP2 is turned on during asthma, and how it contributes to disease development. This information will be essential for designing optimal strategies for drug targeting of the aP2 pathway in asthma.Read moreRead less
The Efficacy And Safety Of Acupuncture For Seasonal Allergic Rhinitis: A Prospective, Randomised Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$175,732.00
Summary
Seasonal allergic rhinitis, also known as hay fever, is a common condition with high prevalence in Australia, being most pronounced during spring and early summer when pollen counts are highest. There is no proven cure for hay fever. Many hay fever sufferers seek alternative therapies such as acupuncture. We propose to undertake a rigorous study, using well-established clinical trial methodology, to evaluate the efficacy and safety of acupuncture in the treatment of hay fever.
Functional Analysis Of The Ym2 Chitinase-like Lectin In Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
The prevalence of asthma is widespread and nationally affects over two million Australians. Consequently, one of the Country s National Health Priorities is to improve our understanding of this condition. Analyses of the asthmatic lung reveal an airway wall that is thickened, an airway lumen that is obstructed and abnormal spasmogenicity of the airway smooth muscle: processes that collectively contribute to both acute and chronic respiratory dysfunction. Asthmatics develop an immune response tha ....The prevalence of asthma is widespread and nationally affects over two million Australians. Consequently, one of the Country s National Health Priorities is to improve our understanding of this condition. Analyses of the asthmatic lung reveal an airway wall that is thickened, an airway lumen that is obstructed and abnormal spasmogenicity of the airway smooth muscle: processes that collectively contribute to both acute and chronic respiratory dysfunction. Asthmatics develop an immune response that is biased toward production of allergy-related T helper 2 cytokines of which interleukin (IL)-13 is a potent mediator of disease. However, the molecular processes linking IL-13 with abnormal airway wall changes are unclear. To identify previously uncharacterised IL-13-related molecules, we used a protein profiling approach that identified a novel lectin (carbohydrate-binding protein) termed Ym2, which is secreted abundantly into the airway fluid of mice in which allergic airways disease has been induced. Preliminary studies suggest that Ym2 is an intermediary of IL-13 that is involved in respiratory dysfunction. This project aims to work out how Ym2 interacts with the molecules and cells of the respiratory tract to regulate allergic disease. Specific inhibitors of Ym2 will be developed to examine what happens to allergic responses when Ym2 can t function; transgenic mice will be developed to determine if we see features of allergy when Ym2 is over-expressed in the normal lung, and human samples will be screened to identify the human counterpart of Ym2 and whether this counterpart is secreted into the lung fluid of asthmatics. Defining the mechanism by which Ym2 regulates the pathogenesis of allergic disease will not only contribute to our basic understanding of the processes underlying asthma pathology, but also generate new information for better design of therapeutics directed against specific mediators of this debilitating and widespread disease.Read moreRead less
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
Mechanisms Of Nanoparticle-mediated Inhibition Of Asthma
Funder
National Health and Medical Research Council
Funding Amount
$637,921.00
Summary
Ultrafine pollution particles may promote asthma, and there is concern that man-made 'nanoparticles' have a similar effect. Surprisingly, we found that inert toxin-free nanoparticles inhibit asthma. We propose nanoparticles do this by leaving a unique �imprint� in the lung. We will explore how this imprint modifies lung inflammatory and immune regulatory cell function, and investigate particles made from advanced biodegradable polymers as potential therapeutics for inflammatory lung diseases suc ....Ultrafine pollution particles may promote asthma, and there is concern that man-made 'nanoparticles' have a similar effect. Surprisingly, we found that inert toxin-free nanoparticles inhibit asthma. We propose nanoparticles do this by leaving a unique �imprint� in the lung. We will explore how this imprint modifies lung inflammatory and immune regulatory cell function, and investigate particles made from advanced biodegradable polymers as potential therapeutics for inflammatory lung diseases such as asthma.Read moreRead less
Protease-activated Receptors As Potential Drug Targets In Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Asthma is a lung disease that kills about 700 Australians each year and causes widespread morbidity in our community. For people with allergic asthma inhalation of allergens such as those contained in house dust triggers an immune response that causes swelling of the airway wall, overproduction of mucus and bronchial smooth muscle contraction. These effects lead to the narrowing of the airways that makes breathing more difficult in people with asthma. Our research groups have been investigating ....Asthma is a lung disease that kills about 700 Australians each year and causes widespread morbidity in our community. For people with allergic asthma inhalation of allergens such as those contained in house dust triggers an immune response that causes swelling of the airway wall, overproduction of mucus and bronchial smooth muscle contraction. These effects lead to the narrowing of the airways that makes breathing more difficult in people with asthma. Our research groups have been investigating a novel group of proteins, called protease-activated receptors (PARs), and in an exciting development have found that substances that stimulate PARs inhibit allergic airways inflammation in mice, which is a well-established animal model of allergic asthma. This raises the possibility that PAR stimulants may in the future be developed as anti-asthma drugs. However, there are many large gaps in our understanding of airway PARs that need to be filled before their use as anti-asthma drugs can be contemplated. Thus, the current study will address many important questions: Do PAR stimulants always improve allergic inflammation, or are there some doses or times of dosing that worsen allergic inflammation? Stimulants of one PAR, called PAR2, improve allergic inflammation, but what about stimulants of the three other PARs (PAR1, PAR3 and PAR4) that exist in the airways? How do PARs improve allergic inflammation, and which substances and cells are involved? Are PAR stimulants also effective in more complex animal models of allergic inflammation, such as those involving proteolytic allergens (e.g. Der p1 from the house dust mite), respiratory tract viruses, and extended periods of allergen exposure (chronic models) that better reflect the human disease allergic asthma? The answers to these and a range of other questions will significantly improve our understanding of the potential utility of PAR stimulants in the treatment of allergic airways disease.Read moreRead less
How Anti-inflammatory Drugs Differentially Affect The Bronchoprotective Signalling Of Protease-Activated Receptor-2
Funder
National Health and Medical Research Council
Funding Amount
$421,690.00
Summary
Asthma contributes significantly to the burden of ill health and impaired quality of life in Australian communities, and for many measures of asthma, Australia has amongst the highest prevalence when compared with other countries. Furthermore, there is evidence that the prevalence of asthma has increased during the latter part of the 20th century. There is currently no cure for asthma, and the need for better asthma therapies through the discovery of novel targets for drug development has never ....Asthma contributes significantly to the burden of ill health and impaired quality of life in Australian communities, and for many measures of asthma, Australia has amongst the highest prevalence when compared with other countries. Furthermore, there is evidence that the prevalence of asthma has increased during the latter part of the 20th century. There is currently no cure for asthma, and the need for better asthma therapies through the discovery of novel targets for drug development has never been more acute. PAR2 is a receptor that is located on the surface of many cell types in the respiratory tract, including the epithelial cells that line the airway tubes. When PAR2 is stimulated it causes the epithelial cells to produce and release large amounts of PGE2 (prostaglandin E2). PGE2 released from epithelial cells then binds to other proteins such as the prostanoid EP2 receptor located on smooth muscle cells. This causes the airway smooth muscle cells to relax. Drugs that cause airway smooth muscle cells to relax - called bronchodilators - make breathing easier, and are often used during an asthma attack to relieve bronchoconstriction. It also appears that activation of the PPP axis inhibits airway wall swelling (that is, has anti-inflammatory actions). Thus, drugs that activate the PPP axis may be beneficial in the treatment of asthma by reducing airway sweeling and producing smooth muscle relaxation. Thus, we we are investigating ways of optimally stimulating the PAR2-PGE2-prostanoid EP2 receptor axis (the PPP axis), as a means of develeping novel treatments for asthma.Read moreRead less