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
Many approaches to the prevention and treatment of allergy and associated asthma are dependent on the identification of the allergens producing the inflammation. This applies to new methods of determining the exposure to allergens and measuring the effectiveness of procedures which minimise allergen exposure. Diagnostic and immunotherapeutic measures require reliable preparations of allergens. The presence of important allergens in extracts however can be variable and often low so it important t ....Many approaches to the prevention and treatment of allergy and associated asthma are dependent on the identification of the allergens producing the inflammation. This applies to new methods of determining the exposure to allergens and measuring the effectiveness of procedures which minimise allergen exposure. Diagnostic and immunotherapeutic measures require reliable preparations of allergens. The presence of important allergens in extracts however can be variable and often low so it important that the allergens be identified and monitored. It is also important that new forms of immunotherapy being developed consider the responses to all allergens. Allergy to the cat is, behind house dust mite, the second most frequent allergy associated with asthma in most developed countries and brief exposure to a cat frequently induces life-threatening attacks. Almost all of the study of cat allergens have concentrated on a single allergen called Fel d 1. Although it importance is undisputed critical reading of the literature show it is only responsible for 50% of the IgE binding in cat extracts and recent work on cross allergy to cat and dogs and experimental therapy based on Fel d 1 point to the importance of other allergens. Experience with other source of allergens has shown that at least several allergens are usually important. It is also apparent from other studies that some allergens which are difficult to detect in extracts, and cannot be readily studied by immunochemistry are important. This project will use both cDNA cloning and immunochemistry to identify and characterize the other cat allergens and determine there relative importance. In particular it intended that they can be used, along with Fel d 1, to develop new types of immunotherapy.Read moreRead less