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Novel Functional Domains On Adrenoceptors For Drug Interaction And Cell Signalling
Funder
National Health and Medical Research Council
Funding Amount
$801,500.00
Summary
Our work involves studying cell-surface proteins (receptors) that respond to hormones such as adrenaline or substances that transmit signals in the nervous system (neurotransmitters). These receptors play a vital role in orchestrating responses to stimuli such as stress, pain, changes in blood pressure, body temperature, fluid and energy status, and exercise. They allow communication between different organs or different parts of the nervous system. G-protein coupled receptors (GPCRs) are the ma ....Our work involves studying cell-surface proteins (receptors) that respond to hormones such as adrenaline or substances that transmit signals in the nervous system (neurotransmitters). These receptors play a vital role in orchestrating responses to stimuli such as stress, pain, changes in blood pressure, body temperature, fluid and energy status, and exercise. They allow communication between different organs or different parts of the nervous system. G-protein coupled receptors (GPCRs) are the major group of cell surface receptors that interact with hormones and neurotransmitters. Treatment of many diseases and conditions relies on the use of drugs that selectively activate or block a single type of GPCR. In fact, about 2-3 of existing therapies are based on these drugs. In designing new drugs it is important to understand as much as possible about the properties of the target receptors. There is emerging evidence concerning interactions between drugs, receptors and proteins inside cells that translate signals into responses (signalling proteins). For example, receptors have additional sites of drug action that can modulate their activity, and can also couple to multiple signalling pathways. We are studying adrenoceptors that respond to adrenaline and to the neurotransmitter noradrenaline. Our studies will use adrenoceptors as model systems to identify novel potential sites for drug interaction, to gain new insights into signalling mechanisms utilized by these receptors and to examine how a variety of phosphorylation mechanisms affect the ability of receptors to couple to particular signalling pathways.Read moreRead less
Molecular Pharmacology Of Beta Adrenoreceptors In Multiple Disease States
Funder
National Health and Medical Research Council
Funding Amount
$578,812.00
Summary
Obesity is a major and increasing health concern for almost half the adult population, and is associated with serious medical conditions including diabetes and heart disease. Changes in behaviour such as increasing physical activity and eating less high-calorie food help many people reduce their body weight, however many others have a genetic predisposition to become overweight and behavioural measures are ineffective. Although anti-obesity drugs should be a valuable adjunct to lifestyle changes ....Obesity is a major and increasing health concern for almost half the adult population, and is associated with serious medical conditions including diabetes and heart disease. Changes in behaviour such as increasing physical activity and eating less high-calorie food help many people reduce their body weight, however many others have a genetic predisposition to become overweight and behavioural measures are ineffective. Although anti-obesity drugs should be a valuable adjunct to lifestyle changes, the currently available appetite suppressants are not ideal. Our work involves studying particular cell-surface proteins (receptors) which normally respond to hormones such as adrenaline. The beta(3)-adrenergic receptor is known to mediate the breakdown of fats and increased heat production in adipose tissue and possibly muscle. Administration of beta(3)-selective drugs to obese mice promotes weight loss and a reduction of diabetic symptoms, and a number of drugs targetting the human beta(3)-adrenergic receptor are being developed by pharmaceutical companies. We are trying to understand more about the properties of this receptor, as this information will assist in designing drugs which are more selective and more potent. Sometimes drugs act at more than one receptor, and there is evidence that this may be the case for two drugs called CGP 12177 and BRL 37344 which stimulate the beta(3)-adrenergic receptor. The second major aim of our project is to find out whether these drugs act at a novel receptor which is related to the beta(3)-adrenergic receptor and also mediates energy expenditure and heat production in adipose tissue and skeletal muscle. The discovery of a new receptor would provide additional scope for the development of effective anti-obesity treatments.Read moreRead less
Molecular Attributes And Physiological Significance Of Beta1L-adrenoceptors
Funder
National Health and Medical Research Council
Funding Amount
$754,353.00
Summary
Beta-blockers are used for the management of cardiovascular diseases including heart failure. We have discovered that one group of beta-blockers not only blocks the receptor but stimulates it. To explain this we hypothesize that human beta-adrenoceptors exist in two different 'states' , high and low. We are now determining whether 1. the low state causes progression of heart failure, 2. the molecular basis of the two states and 3. we can make new compounds to block the low state.
Investigation Of The Mechanisms Involved In Consolidation Of Memory By Beta 3 Adrenoceptoragonists.
Funder
National Health and Medical Research Council
Funding Amount
$241,018.00
Summary
The inability to form new memories is a major and increasingly prevalent health problem for an aging population. In addition to aging, the inability to form new memories is associated with serious medical conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered, but memory does not pass on into permanent storage. We have been able to achieve memor ....The inability to form new memories is a major and increasingly prevalent health problem for an aging population. In addition to aging, the inability to form new memories is associated with serious medical conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered, but memory does not pass on into permanent storage. We have been able to achieve memory consolidation in a particular learning task, which is not normally remembered, by injection of drugs acting on novel receptors (beta 3 adrenoceptors) in the brain of day old chicks. These drugs mimic the action of noradrenaline at beta-3 adrenoceptors. There are a number of ways in which memory consolidation can be enhanced, and we will compare the effects of beta-3 drugs with other potential drugs acting at other types of noradrenaline receptors. One of the actions of beta-3 agonists is related to the uptake of glucose into cells in the brain. We will investigate whether the mechanism of beta-3 enhancement of memory involves the uptake of glucose in brain tissue and studies in cultures of individual cell types will show us which cells are involved. Although this work is done using young chicks, there is no reason to suppose that the basic memory mechanisms at the level of the nerve cell should be different in birds or mammals. There are distinct advantages to using chicks in this research as they can form a long lasting memory for an experience lasting only 10 seconds, and they will discriminate between different colours as part of their learning. This research is aimed at understanding the processes involved in and influencing memory formation. If we are going to develop drugs to alleviate the cognitive problems of old age and more serious cognitive diseases, we need to understand more about the basic mechanisms of memory formation in the normal animal.Read moreRead less