Muscarinic Receptor Signalling, Transglutaminase And Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$518,210.00
Summary
Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of di ....Diabetes is a major and increasing cuase of death and disability in our society. This studies aims to understand the cellular and molecular mechaisms controlling insulin secretion from the pancreas, since defects in this secretion are involved in causing diabetes. The proposed studies are of relevance to both juvenile and adult-onset diabetes, and may lead to new treatment modalities, as well as potentially being relevant to the use of pencreatic islet cell transplantation in the treatment of diabetes.Read moreRead less
Novel Aspects Of Angiotensin AT1 Receptor Signalling Pathways
Funder
National Health and Medical Research Council
Funding Amount
$219,750.00
Summary
Hormones are chemicals released into the blood to influence tissue function by binding to specific sites (receptors) located on the cells found in a particular tissue. In general, it has been considered that a specific receptor activates a specific response when bound by the hormone. However, it is now clear that closely related hormones can activate different patterns of response even when they bind the one type of receptor. The full consequence of this phenomenon is still unknown. Its signific ....Hormones are chemicals released into the blood to influence tissue function by binding to specific sites (receptors) located on the cells found in a particular tissue. In general, it has been considered that a specific receptor activates a specific response when bound by the hormone. However, it is now clear that closely related hormones can activate different patterns of response even when they bind the one type of receptor. The full consequence of this phenomenon is still unknown. Its significance will be investigated in this project for important hormones which are involved in blood pressure control. The renin-angiotensin system makes the hormone angiotensin II which increases blood pressure through actions the heart, blood vessels, nerves and kidneys. One particular receptor type, the AT1 receptor, is responsible for the majority of effects of angiotensin II on these tissues and drugs that inhibit the activity of this receptor are very useful therapies for diseases such as hypertension and heart failure. However, Angiotensin III is a second hormone of the renin-angiotensin system that may also have important effects on tissue function when it activates the AT1 receptor. We have evidence that the type of tissue response that results from angiotensin III activated AT1 receptors is different from the response that results from angiotensin II activation of the same receptors. This raises the possibility that the effects of the AT1 receptor in cardiovascular disease might be differentially promoted by the two angiotensins. This project will investigate the mechanisms by which angiotensin II and anagiotensin III can elicit different activation via the AT1 receptor, and will determine the consequences of this differntial activation to tissue function.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
Alteration Of Glucose Metabolism By GPCR Activation
Funder
National Health and Medical Research Council
Funding Amount
$444,796.00
Summary
In type 2 diabetes the effect of insulin to stimulate glucose transport in fat cells and skeletal muscle is impaired so there is great interest in identifying insulin-independent mechanisms that increase glucose transport. Several G protein-coupled receptors (GPCRs) regulate glucose transport independently of insulin but the mechanisms involved in these effects are largely unknown. This project investigates how GPCRs regulate glucose homeostasis and will evaluate them as potential treatments.
Urotensin-II In Human Heart: Investigation Of Mechanisms Involved In Cardiac Function
Funder
National Health and Medical Research Council
Funding Amount
$255,990.00
Summary
The normal function of the body is maintained by naturally occurring compounds. Some for example affect the heart, fine tuning it to make it beat faster or slower, or beat with greater or less force when required in different situations in health and disease. We were the first to show just recently that a small protein which occurs naturally in the body, called urotensin-II can affect the way the heart beats. We showed that extremely tiny amounts increase the force of the heart beat. Our finding ....The normal function of the body is maintained by naturally occurring compounds. Some for example affect the heart, fine tuning it to make it beat faster or slower, or beat with greater or less force when required in different situations in health and disease. We were the first to show just recently that a small protein which occurs naturally in the body, called urotensin-II can affect the way the heart beats. We showed that extremely tiny amounts increase the force of the heart beat. Our findings indicate that urotensin-II is the most potent heart stimulator identified to date. In patients with heart failure, short term stimulation of heart contraction is beneficial, supplying the heart and other organs with vital oxygen and nutrients. However, in the long term excessive stimulation causes worsening of the patients condition. Very little is currently known about the way in which urotensin-II alters heart function. The goal of our study is to understand the mechanism involved in urotensin-II mediated effects on the heart. This will involve identifying the location of urotensin-II and its receptors in the heart, and determining what signalling changes occur after the interaction of urotensin-II with its receptors. Urotensin-II must first be cleaved from a larger drug. We will determine where in the heart this cleavage occurs and whether the process is crucial to the ability of urotensin-II to stimulate contraction of the heart. Since stimulators of heart contraction are detrimental to patients with heart failure in the long term, we will determine whether these patients have more urotensin-II in their blood than patients who do not have heart failure. If the levels of urotensin-II are higher in heart failure patients, it may indicate a need to interfere with the interaction of urotensin-II with its receptors.Read moreRead less
The Role Of Cellular Microdomains In G-protein Coupled Receptor Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$385,297.00
Summary
Molecules communicate with cells by attaching to proteins called receptors on the outside of cells, and triggering a series of events inside the cell. These events initially include the assembly of multiple proteins at the cell surface. This project will examine the formation of receptors and other proteins into these ‘communication complexes’. This will provide novel targets for more selective drug development.