The Role Of Cbl Proteins In Mast Cell Signalling And Function.
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Allergies such as asthma are caused by cells known as mast cells and basophils. These cells cause allergies because they possess pre-formed granules that contain mediators of allergic reactions, such as histamine, which are released when the cells are activated by allergens. Understanding how this activation occurs, and the biochemical mechanisms that allow the release of allergic mediators, are important steps towards identifying ways to intervene and control allergic responses. The key event t ....Allergies such as asthma are caused by cells known as mast cells and basophils. These cells cause allergies because they possess pre-formed granules that contain mediators of allergic reactions, such as histamine, which are released when the cells are activated by allergens. Understanding how this activation occurs, and the biochemical mechanisms that allow the release of allergic mediators, are important steps towards identifying ways to intervene and control allergic responses. The key event that activates the release of allergic mediators is the binding of environmental allergens to a particular type of antibody called IgE that can bind to a specific receptor on the surface of mast cells and basophils. These IgE-bound receptors transmit strong biochemical signals into the cell which causes a cascade of events resulting in many proteins being biochemically modified and recruited to sites of functional activity. One group of proteins, known as tyrosine kinases, are at the front line of this cascade and they function by targeting and modifying a wide range of other proteins so they become functionally active. Indeed if it were not for tyrosine kinases there would be no signal leading to degranulation of mast cells and basophils and therefore no allergic reactions. Therefore if it were possible to regulate the activity of tyrosine kinases we would be able to control the severity of allergic reactions. For many years we have been studying a protein called Cbl that functions in cells to negatively regulate many tyrosine kinases, including those present in mast cells and basophils. In this grant we aim to investigate whether by deregulating Cbl function in mast cells, derived from mice with mutated forms of Cbl, we can change the activity of tyrosine kinases and thus alter the magnitude of allergic responses. This will determine whether Cbl is candidate target protein for controlling allergies.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