MECHANISMS OF CEREBROVASCULAR REGULATION IN HEALTH AND DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$216,430.00
Summary
Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent and significant research at the basic level to better understand mechanisms of normal, and then abnormal, regulation of cerebral artery function. The project will examine the importance of a novel mechanism in regulating brain blood flow by affecting the ....Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent and significant research at the basic level to better understand mechanisms of normal, and then abnormal, regulation of cerebral artery function. The project will examine the importance of a novel mechanism in regulating brain blood flow by affecting the degree of opening of the cerebral arteries. This mechanism involves activation of an enzyme, Rho-kinase, which is present in the wall of blood vessels. The applicants believe that this process plays an important role in the normal, healthy regulation of blood supply to the brain. Moreover, there are strong reasons for us to speculate that the function of this enzyme is abnormally high in two disease states that are associated with an increased risk of stroke - high blood pressure and subarachnoid haemorrhage. We will employ a variety of techniques to assess the importance of Rho-kinase in cerebral artery function in the living body, and also in isolated segments of artery. The results are expected to provide major new insight into mechanisms that regulate brain blood flow, and the knowledge gained here may lead to better therapies to prevent or treat stroke.Read moreRead less
Ankle Brachial Index Determination By Oscillometric Method IN General Practice (ABIDING)
Funder
National Health and Medical Research Council
Funding Amount
$128,935.00
Summary
People who have peripheral arterial disease (PAD) have blockages of the circulation to their legs. If you have PAD you have blood vessel disease throughout the body and are very likely to have a heart attack or experience a stroke. PAD can be diagnosed simply by comparing the blood pressure in the arms and legs. Until now this needed a special costly instrument. New blood pressure machines can do this without this instrument. We want to know how reliably this can be done by practice nurses.
The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing enzyme responsible for matching energy supply to energy demand by the many different cells in our bodies. AMPK is active in the heart, where it may control cardiac function and the response of the heart to disease. It has been difficult to study AMPK in the heart because we lack drugs that block the actions of AMPK. This study will investigate the role of AMPK in the heart using a genetic approach whereby the AMPK enzyme is re ....The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing enzyme responsible for matching energy supply to energy demand by the many different cells in our bodies. AMPK is active in the heart, where it may control cardiac function and the response of the heart to disease. It has been difficult to study AMPK in the heart because we lack drugs that block the actions of AMPK. This study will investigate the role of AMPK in the heart using a genetic approach whereby the AMPK enzyme is rendered inactive (a gene knockout approach). By this approach we will learn how AMPK controls heart function and how drugs that affect AMPK may impact on the heart.Read moreRead less
Nox4-containing NADPH-oxidase As A Protective Enzyme In The Cerebral Circulation
Funder
National Health and Medical Research Council
Funding Amount
$515,812.00
Summary
Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in a stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent research at the basic level to better understand the processes of normal, and then abnormal, regulation of brain artery function. The project will test the importance of a newly discovered mechanism for increasing brain blood flow. This involves activa ....Failure of the cerebral circulation to meet the brain's immediate high nutritive requirements results in a stroke in just a few minutes. Stroke continues to be a major cause of death and disability, and this major medical challenge requires urgent research at the basic level to better understand the processes of normal, and then abnormal, regulation of brain artery function. The project will test the importance of a newly discovered mechanism for increasing brain blood flow. This involves activation of an enzyme, Nox4-containing NADPH-oxidase, to generate oxygen radicals which then relax the wall of blood vessels causing the arteries to let more blood through. We believe that this process plays an important role in the normal, healthy maintenance of blood supply to the brain. Furthermore, we propose that the activity of this enzyme is elevated and therefore protective in brain arteries during high blood presure - which is the major risk factor for stroke. We will specifically test whether the activity of this enzyme actually helps to limit the amount of brain death following stroke. We will use a variety of techniques to assess the importance of this enzyme in brain arteries in the living body, and also in isolated segments of brain artery from animals that are either healthy or have diseased brain arteries. The results are expected to provide major new insight into processes that help maintain brain blood flow under normal conditions and after a stroke, and the knowledge gained here should lead to safer therapies to prevent or treat stroke.Read moreRead less
The proportion of the population over 65 years of age is increasing, and cardiovascular disease (CVD) is a leading cause of disability and death in this group of people. Angina, heart failure and stroke in elderly people often result in considerable disability and in many instances in a need for changed living circumstances such as admission to nursing homes. Consequently there is an important need to understand how to prevent and manage cardiovascular diseases in elderly people. Although CVD oc ....The proportion of the population over 65 years of age is increasing, and cardiovascular disease (CVD) is a leading cause of disability and death in this group of people. Angina, heart failure and stroke in elderly people often result in considerable disability and in many instances in a need for changed living circumstances such as admission to nursing homes. Consequently there is an important need to understand how to prevent and manage cardiovascular diseases in elderly people. Although CVD occurs much more frequently in older persons, much of the epidemiological information on CVD risk factors and risk estimation comes from studies of middle-aged populations. Recently there has been an increased focus on whether the established relationships hold or differ in the elderly. This has generated debate about the relative value and effectiveness of treating risk factors in elderly people. This study, which is based on comprehensive and long-term risk factor, mortality and morbidity data from the Busselton Health Study and Health in Men Study, will lead to a better understanding of classic and new CVD risk factors in older persons and will contribute positively to the debate about the relative value and effectiveness of attempting to modify risk factors in the elderly. Further, it will facilitate improved methods for CVD risk assessment in older people and hence assist in determining whether which preventive actions to implement in the elderly.Read moreRead less
Genetic Markers For Retinal Arteriolar Narrowing And Risk Of Hypertension And Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$438,991.00
Summary
This submission proposes a study to identify the genes that determine retinal arteriolar narrowing - a marker of hypertension, and to examine how these genes interact with environmental factors, and to investigate if these genes do indeed predict persons at risk of heart disease.
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
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.
Salt And Cardiovascular Disease: Does Acute Salt-Sensitivity Convey Greater Cardiovascular Risk?
Funder
National Health and Medical Research Council
Funding Amount
$597,578.00
Summary
Salt intake of Australian adults is 10X more than required. Further, salt intake in very young children is alarmingly high secondary to high consumption of salty snacks and processed food. High dietary salt intake has been associated with increased cardiovascular disease and death. We will examine the cardiovascular risks for adults and children on a high salt diet and examine whether switching to a low salt diet ameliorates the high blood pressure and heart disease caused by high salt diets
Role Of Advanced Glycation End Products And Their Receptors In Diabetes Accelerated Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$389,521.00
Summary
Diabetes is on the increase in the Western world and with this increase comes the burden of increased complications. One of these is atherosclerosis which leads to heart attacks, strokes and gangrene. In this grant we consider the role of a biochemical reaction where sugar attaches to proteins called advanced glycation and how these advaced glycated proteins (AGEs) interact with specific receptors to promote atherosclerosis. We will use novel animal models overexpressing the receptor RAGE or wit ....Diabetes is on the increase in the Western world and with this increase comes the burden of increased complications. One of these is atherosclerosis which leads to heart attacks, strokes and gangrene. In this grant we consider the role of a biochemical reaction where sugar attaches to proteins called advanced glycation and how these advaced glycated proteins (AGEs) interact with specific receptors to promote atherosclerosis. We will use novel animal models overexpressing the receptor RAGE or with deletion of the gene for this receptor. We will investigate if these animals are protected against blood vessel disease when made diabetic and will unravel the mechanisms involved. Furthermore we will investigate novel drugs to block vessel damage in a model of diabetic mice prone to atherosclerosis. One of these interventions will involve giving a free form of the receptor RAGE which will trap the circulating AGEs and prevent them from binding to RAGE in the blood vessel wall. This therpeutic principle has been shown in animals to prevent blood vessel disease in diabetes. We will also feed the sugar-attached proteins (AGEs) to these mice prone to atherosclerosis and to the genetically modified mice to see how these proteins directly influence the vessel wall even if diabetes is not present. These studies will ultimately lead to better treatments to prevent, slow down or reverse blood vessel damage in diabetes.Read moreRead less