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.
NOVEL CGMP-BASED THERAPIES PREVENT LEFT VENTRICULAR REMODELLING
Funder
National Health and Medical Research Council
Funding Amount
$533,433.00
Summary
Over 300,000 Australians are affected by heart failure. Current drugs for cardiac remodelling (the decline in heart pumping function and changed structure that precede heart failure) slow but not reverse disease progression. We have identified a new, nitrovasodilator-based therapy superior to those currently available. We propose it represents a more effective treatment for reversing abnormalities in both structure and function in the remodelled heart, preventing or delaying heart failure.
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
TARGETING ROS-INDUCED DAMAGE RESCUES THE DIABETIC HEART
Funder
National Health and Medical Research Council
Funding Amount
$487,669.00
Summary
Over 1 million Australians have diabetes. Many of these patients die from cardiovascular disease. We have identified free radicals as a major cause of decreased pumping function and impaired recovery from each heartbeat in the diabetic heart. Stronger antioxidant approaches and-or activation of protective protein pathways is a more effective treatment for reversing impaired function in the diabetic heart, preventing or delaying heart failure in patients with diabetes.
Contractile And Relaxant Effects Of B2- And B1-adrenoceptors In Human Heart: Blockade By A Third Generation B-blocker
Funder
National Health and Medical Research Council
Funding Amount
$136,320.00
Summary
The force and the duration of each heart beat can be modified in disease states affecting the heart. They can also be modified by chemicals which occur naturally in the body. Two of the most important naturally occurring chemicals which affect the function of the heart are (-)-noradrenaline and (-)-adrenaline. These chemicals and others which have been synthesized and optimized can also be used therapeutically. They work by activating proteins which occur on the cell surface, called b-adrenocept ....The force and the duration of each heart beat can be modified in disease states affecting the heart. They can also be modified by chemicals which occur naturally in the body. Two of the most important naturally occurring chemicals which affect the function of the heart are (-)-noradrenaline and (-)-adrenaline. These chemicals and others which have been synthesized and optimized can also be used therapeutically. They work by activating proteins which occur on the cell surface, called b-adrenoceptors. When activated, b-adrenoceptors cause an increase in the force of each heart beat and a reduction in the duration of each heart beat. This may be an advantage in conditions where the heart beat is too long. In this study we propose to map the biochemical pathways through which b-adrenoceptors affect each heart beat. The therapeutic management of heart failure has been revolutionized by the use of compounds which block b-adrenoceptors. One such drug, carvedilol is currently used in this country. The way in which it works may not be fully understood. In preliminary experiments we have identified a novel mechanism for carvedilol directly in human heart in which it may work and contribute to it's beneficial effects in the management of heart failure. Our studies will focus on this finding.Read moreRead less
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
Studies Of Metabolites Of Synthetic Flavonols For The Treatment Of Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$207,440.00
Summary
Cardiovascular disease, including heart attack and stroke, is the leading killer of Australians. A promising new drug, NP202, can reduce the amount of tissue damaged from a heart attack; however, its mechanism of action remains obscure. NP202 is metabolized to a range of compounds, one of which is partly responsible for its beneficial effects. In this project we will identify other metabolites of NP202 and characterize their biological activity to gain insight into its mechanism of action.
NADPH Oxidase In Pathological Angiogenesis In Solid Tumours And Retina
Funder
National Health and Medical Research Council
Funding Amount
$581,989.00
Summary
Understanding blood vessel growth has profound clinical implications for many diseases. Blocking vessel growth is a promising strategy for treatment of cancer and eye complications accompanying diabetes, whereas treatments to stimulate new vessel growth will treat ischemic disorders ie. heart attack and stroke. Here we investigate whether targeting an enzyme that grows blood vessels has potential for making drugs to stop tumor growth or eye damage that occurs with diabetes and premature births.