Probing Changes In G Protein-coupled Receptor Signalling Networks During Breast Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$892,733.00
Summary
The b2-adrenoceptor is a protein receptor that enables cells to respond to hormones. In breast cancer, this receptor causes more aggressive tumour cells to metastasise faster in response to stress. This proposal aims to understand why this response occurs in only very aggressive cells, and to identify how we can better target blocking drugs to this receptor. This could allow us to design better drugs with fewer side effects.
Elucidation Of The Molecular Requirements Of The Low Affinity 'state' Of The Beta1-adrenoceptor
Funder
National Health and Medical Research Council
Funding Amount
$535,500.00
Summary
Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to blo ....Beta-blockers are used for the management of cardiovascular diseases including heart failure, ischaemic heart disease and high blood pressure. Beta-blockers mostly work by blocking the effects of a naturally occuring chemical called noradrenaline. Beta-blockers can be used to prevent noradrenaline induced increases in the rate and force of human heart contraction. We have discovered that one group of beta-blockers exemplified by CGP 12177 has the remarkable property of not only being able to block beta-receptors but they can also stimulate them at higher concentrations. Thus low concentrations block the effects of noradrenaline, but higher concentrations stimulate the receptor. More puzzling is that the stimulant effects of this group of beta-blockers cannot be easily blocked. To explain this we hypothesize that human beta-receptors can exist in two different 'states'. One 'state' can be stimulated by noradrenaline and blocked by low concentrations of beta-blockers such as propranolol and CGP 12177. Another 'state' of the same receptor is resistant to blockade by beta-blockers such as propranolol but can be stimulated by beta-blockers such as CGP 12177. This project seeks to investigate the molecular basis of the beta-adrenoceptor that is responsible for stimulant effects of beta-blockers. Specifically it explores the components of the beta-adrenoceptor that are critically and uniquely important for interacting with the stimulant beta-blockers. This project is an important increment in our laboratories research program to increase our understanding of the effects of beta-blockers. Our long term goal is to be able to develop beta-blockers that can block both states of the beta-adrenoceptor to provide a more effective block of the receptor and in particular for the improved management of heart failure.Read moreRead less
Novel Muscle Therapeutics Through Selective Beta-Adrenoceptor Signalling
Funder
National Health and Medical Research Council
Funding Amount
$603,608.00
Summary
Muscle wasting is an urgent and unmet health risk commonly associated with ageing; cancer, muscle diseases, and conditions including cardiovascular and metabolic disorders. Manipulating beta-adrenergic signalling is a therapeutic target for muscle wasting but treatments have so far been limited due to cardiaovascular side effects. Using cutting edge technologies, we will identify treatments that effectively separate beneficial effects on skeletal muscles from unwanted effects on the heart.
Novel Actions Of Beta-adrenoceptor Antagonists: Implications For The Treatment Of Cardiac Failure
Funder
National Health and Medical Research Council
Funding Amount
$142,630.00
Summary
Almost 2-3 of drugs on the market act on G protein-coupled receptors, and many are antagonists that block receptors. Antagonists were seen as inert compounds that prevent access of natural neurotransmitters or hormones, but recent studies indicate distinct actions. We believe that atypical effects of beta-adrenergic antagonists may explain their usefulness in treating cardiac failure. We seek to understand the process and develop assays to aid the development of new drugs for cardiac failure.
Targeting Beta-adrenergic Signalling To Improve Muscle Regeneration In Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$473,224.00
Summary
Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy, caused by a lack of a protein called dystrophin. Dystrophic muscles are fragile, prone to injury, and have a compromised ability to regenerate after damage. Modulating pathways regulating beta-adrenergic signalling has potential to attenuate the dystrophic pathology and to delay the onset or slow the progression of the muscle wasting and weakness in muscular dystrophy.
Exploring The Pluridimensionality Of Drug Efficacy.
Funder
National Health and Medical Research Council
Funding Amount
$326,184.00
Summary
Dysfunction of cell surface receptors is the underlying cause of many pathological conditions. Using cell based screening methods we aim to investigate the mechanisms underlying drug action, to understand how drugs acting at common targets promote distinct biological responses. This will aid the development of new therapeutics based on the ability to predict specific drug effects.
Diabetes mellitus is a disease reaching epidemic proprotions in the western world. Nearly one million Australians have diabetes mellitus; many of these people will suffer debilitating secondary complications, resulting in significant morbidity and mortality at considerable social and economic cost. Complications include heart attack, stroke, kidney disaease, blindness and limb amputation. There are two forms of diabetes (type I and type 2), and though there are considerable differences in their ....Diabetes mellitus is a disease reaching epidemic proprotions in the western world. Nearly one million Australians have diabetes mellitus; many of these people will suffer debilitating secondary complications, resulting in significant morbidity and mortality at considerable social and economic cost. Complications include heart attack, stroke, kidney disaease, blindness and limb amputation. There are two forms of diabetes (type I and type 2), and though there are considerable differences in their etiology, both forms result in an inability of the body to control blood sugar levels. Beta cells release the hormone insulin, which regulates blood sugar levels. Current knowledge suggests that a loss of beta cell mass is important for both diseases. For type I diabetes the beta cells are destroyed by the immune system. Though for type 2 diabetes the causes are less clear, it is apparent that the beta cells are dying. Our research is focused on understanding the molecular pathways that control beta cell survival and regulate their death. Such knowledge would help us understand the complex processes leading to the development of diabetes. Furthermore, we could use this knowledge in the design of genetic engineering strategies to create 'death-defying' beta cells, as a potential therapeutic strategy for the treatment of diabetes.Read moreRead less