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
Neurodevelopmental Outcome After Sevoflurane Versus Dexmedetomidine/remifentanil Anaesthesia In Infancy: A Randomised Controlled Trial
Funder
National Health and Medical Research Council
Funding Amount
$825,787.00
Summary
Evidence in animals show that some anaesthetics affect the developing brain. Some human data also show a link between childhood surgery and poorer neurodevelopmental outcome. It is unknown if this association is due to the anaesthetic. Our recent GAS trial showed no evidence for toxicity after 1 hour of anaesthesic but many children have longer anaesthetics. We plan to enrol 420 infants in a study comparing neurodevelopmental outcome after 2 different anaesthetics for surgery lasting >2 hours ....Evidence in animals show that some anaesthetics affect the developing brain. Some human data also show a link between childhood surgery and poorer neurodevelopmental outcome. It is unknown if this association is due to the anaesthetic. Our recent GAS trial showed no evidence for toxicity after 1 hour of anaesthesic but many children have longer anaesthetics. We plan to enrol 420 infants in a study comparing neurodevelopmental outcome after 2 different anaesthetics for surgery lasting >2 hours.Read moreRead less
Non-cardiac surgery is associated with significant risk of complications and death, particularly in elderly patients who are known to have heart disease, or who have risk factors for it (ie smoking, high blood pressure). About 11% of the Australian population are currently taking medications for heart disease or high blood pressure and about 80% have at least one risk factor for heart disease. As more than 2 million Australians have general anaesthesia for non-cardiac surgery every year, a subst ....Non-cardiac surgery is associated with significant risk of complications and death, particularly in elderly patients who are known to have heart disease, or who have risk factors for it (ie smoking, high blood pressure). About 11% of the Australian population are currently taking medications for heart disease or high blood pressure and about 80% have at least one risk factor for heart disease. As more than 2 million Australians have general anaesthesia for non-cardiac surgery every year, a substantial group of patients are therefore at risk of an adverse outcome following surgery. Despite the magnitude of this problem, however, few studies have established treatments to decrease the risk of complications and death following surgery. Beta-blockers are a group of drugs which have been used for decades in the treatment of heart disease and high blood pressure. Beta-blockers are known to improve the way the heart copes with the stress of surgery. They decrease the heart rate, make the heart more efficient at using energy and reduce the likelihood of imbalance between oxygen supply and demand. Some previous studies showed that beta-blockers may reduce the risk of heart attack and death for up to 2 years after surgery. However, other studies have shown no effect of beta-blockers on outcome. These previous studies have involved small numbers of patients who may not represent the broader population having surgery. We therefore are undertaking a large trial to definitively answer the question about whether beta-blockers improve the outcome after non-cardiac surgery in patients with, or at risk of, heart disease. Even if the effect of beta-blockers is relatively modest, because such large numbers of patients with heart disease have surgery, the overall effect on the rate of complications and death in the population could be very significant. The results of this study could have major implications for the success of, and cost of, surgery worldwide.Read moreRead less
The Influence Of Anaesthetic Depth On Patient Outcome After Major Surgery
Funder
National Health and Medical Research Council
Funding Amount
$2,893,795.00
Summary
Millions of high-risk patients have general anaesthesia for major surgery worldwide every year, but the optimal depth of anaesthesia for these patients is not known. The aim of this large randomised trial is to determine the impact of light versus deep general anaesthesia on survival at one year postoperatively in 6,500 older patients. If light anaesthesia is associated with better survival, this result will be immediately implementable, will save lives and will reduce the costs of care.
Outcomes From A Multi-site Randomised Controlled Trial Comparing Regional And General Anaesthesia For Effects On Neurodevelopmental Outcome And Apnoea In Infants
Funder
National Health and Medical Research Council
Funding Amount
$757,831.00
Summary
Animal studies suggest general anaesthetics harm the developing brain. It is unclear if these findings are relevant to humans. The aim of this international randomised controlled trial is to determine whether children exposed to general anaesthesia as an infant have a poorer neurodevelopmental outcome. A previous NHMRC grant funded the first phase of the trial along with substantial funding from overseas. The trial will tell us if general anaesthetics affect the developing brain in children.