Characterization Of Mast Cell Basophil Haematopoesis In Patients With Asthma And Drug Allergies.
Funder
National Health and Medical Research Council
Funding Amount
$412,379.00
Summary
The major emphasis of this investigation is to analyse blood for specific cells thought to be implicated in allergic disease from patients undergoing allergic reactions to medications and in patients with asthma and other allergies. Certain cells in the circulation of these patients are thought to be involved in the clinical manifestation seen in patients with asthma and other allergies. These cells have certain characteristics and for the first time our laboratory has identified a particular ce ....The major emphasis of this investigation is to analyse blood for specific cells thought to be implicated in allergic disease from patients undergoing allergic reactions to medications and in patients with asthma and other allergies. Certain cells in the circulation of these patients are thought to be involved in the clinical manifestation seen in patients with asthma and other allergies. These cells have certain characteristics and for the first time our laboratory has identified a particular cell in the circulation of patients with asthma which we believe may be important in the pathogenesis of this condition. We propose to examine these cells in patients with asthma, those experiencing allergic reactions to drugs and other allergies and determine their characteristics and their growth responses to a number of growth factors which have been demonstrated to affect the growth of cells known as mast cells in the test tube. Once we have characterised these cells in terms of what particular proteins and other products they contain we will then try to correlate the number and type of cell with the clinical allergic state of the patient. Blood will be obtained from patients undergoing acute asthma and those in remission to determine if there is any specific relationship of these cells with acute allergic reactions. We will be also looking at how these cells regulate other physiological systems in the body, in particular possible explanations why patients that suffer acute allergic reactions develop significant drops in blood pressure. We can identify these cells with a specific antibody that we have used in our preliminary studies. This antibody binds the surface of these cells, however the specific protein to which this antibody binds has not been identified. We propose to identify this protein by using molecular biology techniques. These studies will provide us with important insights on the nature of these cells and may lead to new therapies.Read moreRead less
IL-16 Regulates Mast Cell Chemotaxis And Function Through The Tetraspanin CD9.
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Mast cells are found in humans and other mammals at strategic sites such as skin, lining of the airways and gut and provide a first line of defence against a variety of infections. These cells use a number of products that have profound effects in humans. In particular, these products are thought to be involved in defence against bacteria, viruses and are implicated in allergic conditions such as asthma. In normal circumstances mast cells are only found in the tissues and not in the peripheral b ....Mast cells are found in humans and other mammals at strategic sites such as skin, lining of the airways and gut and provide a first line of defence against a variety of infections. These cells use a number of products that have profound effects in humans. In particular, these products are thought to be involved in defence against bacteria, viruses and are implicated in allergic conditions such as asthma. In normal circumstances mast cells are only found in the tissues and not in the peripheral blood. However, we have made the first observation that mast-like cells occur in the peripheral blood of patients with asthma and allergic conditions but not in normals. This finding changed the prevailing paradigm for mast cell biology. The products that can influence mast cell growth and function are vital to the understanding of how mast cells are involved in conditions such as human asthma. We have demonstrated that a protein (CD9) on mast cells in the tetraspanin family is a receptor for a product (IL-16) which is thought to be important in asthma and other inflammatory conditions. The understanding of how mast cells are regulated by IL-16 may lead to potential new therapies in conditions such as asthma and HIV-1 infection.Read moreRead less
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
It has recently become apparent that we all make a substance in the lungs called nitric oxide. The amount that we make is increased in diseases such as allergic asthma. This project will study the connection between the allergen being inhaled and the excess nitric oxide being made by cells in the lung. From this research we will have a better understanding of the processess involved and develop better therapies for asthma.
The Role Of RasGRP4, A Mast Cell Specific Protein In Mast Cell Growth, Differentiation And Activation
Funder
National Health and Medical Research Council
Funding Amount
$580,433.00
Summary
Mast cells are cells found in the body which are strategically located at mucosal sites and skin where they form a very important barrier in the immune defence. Mast cells have been implicated in a range of inflammatory disorders such as asthma and more recently they have been shown to participate in immunity against bacteria, viruses and fungi. Although a lot of work has been performed to analyze how mast cells respond to different stimuli and what factors are important in their activation, the ....Mast cells are cells found in the body which are strategically located at mucosal sites and skin where they form a very important barrier in the immune defence. Mast cells have been implicated in a range of inflammatory disorders such as asthma and more recently they have been shown to participate in immunity against bacteria, viruses and fungi. Although a lot of work has been performed to analyze how mast cells respond to different stimuli and what factors are important in their activation, there is little work available concerning what in the mast cell controls it's ability to become a mast cell and not any other cell. We have identified a specific protein that has been designated RasGRP4 which is restricted to mast cells and has, we believe, an important role to play not only in guiding immature cells to become mast cells but also in controlling some of the important functions of mast cells. Understanding this molecule more extensively will give us a much better understanding of diseases that the mast cell is involved in such as asthma and other inflammatory disorders. In addition it may shed insights into how mast cells are involved in immunity against bacteria and viruses.Read moreRead less
Delineation Of The Role Of RasGRP4 In Mast Cell Growth, Differentiation And Activation, Using RasGRP4 Deficient Mice
Funder
National Health and Medical Research Council
Funding Amount
$636,199.00
Summary
Mast cells are important in immunity. Mast cells have been implicated in asthma and more recently they have been shown to participate in immunity against bacteria, viruses and fungi. We have identified a specific protein, RasGRP4, which is restricted to mast cells and plays an important role in their development and function. Understanding this molecule more extensively will give us a much better understanding of diseases that the mast cell is involved in such as asthma and other disorders.