Anti-atherosclerotic Effects Of Angiotensin Fragments & Non-AT1 Receptors: Validation As Innovative Therapeutic Targets
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the horm ....In Australia the largest cause of death is coronary heart disease (CHD) leading to heart attacks or stroke and claiming a staggering 28,000 lives a year. Atherosclerosis is one of the leading causes of cardiovascular disease, with diseased vessels not able to fully dilate and the plaque that has built up inside these vessels impeding blood flow and possibly rupturing, resulting in heart attacks and stroke. One of the major players in the development and progression of atherosclerosis is the hormone, angiotensin II. Angiotensin II has been found to trigger many factors that cause thickening of the vessel wall, inflammation and imbalances in vasodilator capacity (e.g. oxidative stress and endothelial dysfunction), all of which contribute to atherosclerosis. Clinical trials with drugs that inhibit the formation of angiotensin II (ACE inhibitors), or block the action of angiotensin II (angiotensin receptor antagonists), have demonstrated a significant decrease in mortality in patients with high risk for cardiovascular disease. However their mechanism(s) of action are not fully understood as the circulating levels of shorter fragments of angiotensin II (such as Ang IV and Ang (1-7)) are raised in the blood when these drugs are used and may contribute to the protective effects of these drugs. Importantly, we have found that both Ang IV and Ang (1-7) have protective effects in atherosclerotic blood vessels. Therefore, we hypothesise that fragments of angiotensin II (such as Ang IV and others) exert anti-atherogenic effects via distinct binding sites that oppose the effects caused by angiotensin II, and that these may be partly responsible for the cardio-protective effects of the ACE inhibitors and angiotensin receptor antagonists. Thus, information gained in our study will be useful in directing future prescription practices in clinical management of CHD and stroke, and for designing new therapeutic compounds for the management of atherosclerosis.Read moreRead less
Preventing Stroke From Arteriovenous Malformations Using Precision Thrombosis
Funder
National Health and Medical Research Council
Funding Amount
$993,866.00
Summary
Brain arteriovenous malformations are rupture-prone blood vessels that cause stroke in children and young adults. One third of patients have no current treatment options. We aim to develop new medicines that cause blockage of the abnormal vessels, thus preventing them from bleeding and causing stroke. Focused radiation is used to produce molecular changes in the abnormal vessels; these molecules are then the target for the new medicines. We will develop several new drugs for clinical testing.
Mechanisms Of Vascular Dysfunction During Acute And Chronic Hyperglycemia
Funder
National Health and Medical Research Council
Funding Amount
$56,700.00
Summary
Increased consumption of sugary drinks has contributed to an epidemic of obesity and diabetes and consequently cardiovascular disease. For the first time in living memory, this may well lead to declining life-expectancy. My research will examine both the short and long-term impact of sugary drinks on vital blood vessel function. In the process it will develop better methods to monitor blood vessel function and inform public health policy on sugary drinks and preventing cardiovascular disease.
Modulation Of Vegfc/Vegfr3 Signaling At The Extracellular Matrix During Embryonic Lymphangiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$570,928.00
Summary
Lymphatic vessels play important roles in vascular diseases and cancer. However, we are yet to understand how they form during development and disease. We recently identified the gene CCBE1, essential for the formation of lymphatic vessels and responsible for lymphatic dysplasia in humans. This study aims to understand the molecular pathway in which CCBE1 acts. This work aims to characterize new molecular pathways in lymphatic vessels in order to identify new therapeutic targets in lymphatic dis ....Lymphatic vessels play important roles in vascular diseases and cancer. However, we are yet to understand how they form during development and disease. We recently identified the gene CCBE1, essential for the formation of lymphatic vessels and responsible for lymphatic dysplasia in humans. This study aims to understand the molecular pathway in which CCBE1 acts. This work aims to characterize new molecular pathways in lymphatic vessels in order to identify new therapeutic targets in lymphatic disease and cancer.Read moreRead less
Regulation Of VEGFR Trafficking And Signal Transduction By The Ubiquitin Ligase Nedd4
Funder
National Health and Medical Research Council
Funding Amount
$388,347.00
Summary
Our recent work has discovered that the Nedd4 gene is crucial for the growth and development of blood vessels and lymphatic vessels. Our data suggest that Nedd4 controls vessel growth by regulating the levels and signalling activity of the key vascular growth factor receptors VEGFR-2 and VEGFR-3. The goals of this proposal are to define precisely how Nedd4-1 regulates the activity of these receptors and how VEGFR signalling could be better targeted to treat vascular disorders.
Role Of Microparticles In Cardiac Ischemia Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$55,575.00
Summary
Interventional cardiology has reduced the mortality rate associated with heart attack, unfortunately the prevalence of heart failure has subsequently increased, caused in part by reperfusion injury of previously occluded vessels. We aim to identify novel insights into the pathogenesis of IR injury in the heart, as well as the development of new approaches to prevent cardiac damage during cardiac surgery, transplantation, post-angioplasty and coronary artery stenting.
Uncovering A Novel Genetic Interaction That Governs Blood Vessel Development In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$626,557.00
Summary
Blood vessels are a vital component of the cardiovascular system. Abnormalities in the growth and development of blood vessels are associated with human disorders including cardio-vascular disorders, cancer and inflammatory diseases. The focus of this application is to determine the molecular events that direct the construction of the blood vascular tree, with the aim of identifying targets to which novel therapeutics for the treatment of blood vascular diseases could be generated.
Oxidative Stress, Heparan Sulfates And Endothelial Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$450,390.00
Summary
During vascular disease endothelial cells that line the blood lumen are dysfunctional. Growing evidence indicates a role for a protein that the immune system normally uses to destroy infectious agents. This protein accumulates in diseased blood vessels next to endothelial cells. This project will study how this protein causes endothelial dysfunction and test the ability of novel agents to remove this protein from diseased blood vessels to improve endothelial function.
Vascular Effects Of Exercise Training And Lipid-lowering Therapy At Rest And During Exercise In Hypercholesterolaemia
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
The health of the cells which line blood vessels, endothelial cells, is now known to be important in maintaining normal function of the circulation. In patients with elevated blood cholesterol concentration, the function of these cells is abnormal and this is considered to contribute importantly to the blood vessel dysfunction and cardiovascular disease seen in this condition. We have recently demonstrated that drug therapy aimed at decreasing cholesterol concentration in the blood can significa ....The health of the cells which line blood vessels, endothelial cells, is now known to be important in maintaining normal function of the circulation. In patients with elevated blood cholesterol concentration, the function of these cells is abnormal and this is considered to contribute importantly to the blood vessel dysfunction and cardiovascular disease seen in this condition. We have recently demonstrated that drug therapy aimed at decreasing cholesterol concentration in the blood can significantly improve blood vessel function. In other studies we have demonstrated that exercise training improves blood vessel function. The purpose of this research is to determine whether high blood cholesterol impairs exercise capacity by limiting blood flow to exercising muscle. It is also our goal to determine whether exercise training can produce benefit additional to that resulting from lowering cholesterol in those with initially high cholesterol. Blood vessel function will be studied at rest, in response to pharmacological stimulation and during exercise. Vascular function in the forearm will be assessed using synchronised ultrasound (high frequency sound, sonar) and Doppler measures which assess the size of, and flow in, the large artery near the elbow crease. During measurements, procedures are undertaken to alter flow in the arm blood vessels, some depending upon functional ability of the endothelial cells and some independent of those cells. In addition to assessment of blood vessel function, measurements of exercise tolerance will be taken before and after each intervention. By examining the effects of lipid-lowering and exercise training on rest and exercise blood flow responses, this research will help determine the best approach to improving blood vessel function and cardiovascular fitness in patients with high cholesterol.Read moreRead less
Understanding How GATA2 Controls Lymphatic Vessel Valve Development
Funder
National Health and Medical Research Council
Funding Amount
$697,942.00
Summary
Mutations in the GATA2 gene cause human lymphoedema as a result of the crucial role that GATA2 plays in controlling the expression of genes important for building functional lymphatic vessels. Here we aim to gain a complete picture of the cellular and molecular events that are controlled by GATA2 in lymphatic vessels and in particular, in lymphatic vessel valves.