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
This project will characterise the biological and functional properties of a novel human pro-inflammatory S100 protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells. These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location makes them prime targets to trigger vascular and inflamma ....This project will characterise the biological and functional properties of a novel human pro-inflammatory S100 protein. The protein is a natural component of the innate immune system and is regulated in cells by mediators of inflammation and infection. Our preliminary experiments indicate that this protein can activate mast cells. These cells reside in almost all body tissue and are located close to blood vessels and nerves. This location makes them prime targets to trigger vascular and inflammatory events. They are known to be important in allergy and infection and have a proposed role in chronic inflammatory processes. Although the mechanisms of mast cell activation contributing to acute responses in allergic reactions are well accepted, ways in which they are activated in asthma and other chronic inflammatory disease are virtually unknown. We will use lung biopsies from patients with asthma to detect patterns of expression of the protein and determine its effects on lung mast cells. A murine model will be used to define the characteristics of inflammation induced by the S100 protein and the role of mast cells in this process. Structural studies will define the parts of the protein necessary for mast cell activation. We will attempt to identify its receptor on mast cells to enable future studies to define how the protein triggers the cells to produce mediators such as histamine and those causing blood vessel changes. This knowledge could lead to design of novel drugs that could regulate this process. Results from this project will provide new knowledge of chronic inflammatory processes and could result in designing novel strategies to regulate these. Studies are relevant to infectious diseases and many other conditions with a chronic inflammatory basis, including asthma, rheumatoid arthritis, cardiovascular disease, cystic fibrosis and infection.Read moreRead less
Novel Approaches To Control Mast Cell Function In Allergic Inflammation.
Funder
National Health and Medical Research Council
Funding Amount
$723,447.00
Summary
Allergic disorders are a major health problem. Driven by mast cells, the underlying inflammation is exacerbated by the ‘?c family’ of cytokines acting on the surface of these cells. We aim to characterise the ‘mast cell-?c axis’ with the view to developing new therapies based on our ?c receptors blocking antibodies. This path of discovery-mechanism-translation seeks to recapitulate our previous success of taking a related antibody to Phase II clinical trials to treat patients with leukaemia.
Synovial Macrophages And T-cells Are Therapeutic Targets In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$658,761.00
Summary
Osteoarthritis (OA) is the most widespread musculoskeletal disease in Australia and there are currently no therapies that halt disease progression. Specific inflammatory events play a pivotal role in initiating and driving OA progression. In this study we will define the specific inflammatory cells involved in OA, how and why they change with time, and which can be targeted to stop disease onset and development. This will provide the platform for initiating human clinical trials.