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.
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.
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
Identification Of The Molecular Genetic Basis Of The Hepatic Veno-occlusive Disease With Immunodeficiency Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight fam ....One of the most serious complications of bone marrow transplantation is veno-occlusive disease (VOD), also termed sinusoidal obstruction syndrome (SOS). This condition occurs in 10% of transplanted patients and is characterised by abnormalities of liver function, enlargement of the liver, clotting abnormalities, fluid retention and finally failure of multiple organs and death in 30-50% of cases. The cause of VOD is unknown, and its occurrence cannot be predicted in individual patients. Eight families have been described in whom a number of individuals have succumbed to a condition which is clinically and histologically indistinguishable from VOD. Affected individuals also have a form of immunodeficiency (hence termed VODI), and the abnormalities are inherited in an autosomal recessive pattern. All eight are of Lebanese origin, suggesting that a single genetic ancestral mutation was responsible for the disorder in all families, who are distantly related. We have access to genetic material from three of these families, and are on the way to identifying the causative genetic abnormality. We hypothesise that understanding this abnormality will lead to an understanding of VOD which occurs after bone marrow transplantation. We have used 800 polymorphic genetic markers scattered throughout the genome to identify the location of the genetic abnormality, and have localised the defect to a region of chromosome 2 which contains approximately 37 known and predicted genes. We now aim to determine which of the gene(s) in the candidate region is responsible for VODI, and plan to examine DNA from individuals who have had VOD after transplantation to determine if they have a related abnormality. Finding the VODI gene will benefit these families through the availability of carrier detection and may also lead to an understanding of the veno-occlusive disease that occurs after bone marrow transplantation.Read moreRead less
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.
Local Microvascular Regulatory Mechanisms In Diabetes: Relevance To Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
In diabetes mellitus, the excessive levels of sugar in the blood may cause changes in metabolic processes within cells that lead to disturbances in the function of the circulatory and nervous systems. Such disturbances have been shown to occur in the early stages of diabetes and ultimately lead to longterm consequences including poor wound healing (often culminating in limb amputations), increased risk of blindness, kidney disease and heart failure. At present it is not possible to restore norma ....In diabetes mellitus, the excessive levels of sugar in the blood may cause changes in metabolic processes within cells that lead to disturbances in the function of the circulatory and nervous systems. Such disturbances have been shown to occur in the early stages of diabetes and ultimately lead to longterm consequences including poor wound healing (often culminating in limb amputations), increased risk of blindness, kidney disease and heart failure. At present it is not possible to restore normal metabolism, leaving patients at risk of developing complications involving the circulatory and nervous systems. An understanding of the processes involved in the development of such complications would allow alternate treatment strategies to be devised in order to improve the quality of life and life expectancy of diabetic patients. The events leading to abnormalities in the function of the circulatory and nervous systems are uncertain, however, studies have demonstrated that in diabetes there may be an insufficient blood supply to nerves and this would be expected to cause nerve damage. At present, our understanding of the factors involved in regulating blood flow to nerves is limited. The studies described in this proposal are aimed at testing the hypothesis that nerve blood vessels are themselves involved in the regulation of flow through an intrinsic ability to change their diameter in response to tissue demands and that in diabetes alterations in the capacity of nerve blood vessels to constrict or dilate compromises their role in the control of nerve blood flow . Information obtained from these studies will improve our understanding of the early disturbances in the function of circulatory and nervous systems leading to alterations in blood flow which precede the development of overt changes characteristic of the complications associated with diabetes. This will provide insight into developing new treatment strategies for diabetic patients.Read moreRead less
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.