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.
Early Events In Arteriolar Remodeling: Adaptation To Prolonged Vasoconstriction
Funder
National Health and Medical Research Council
Funding Amount
$415,750.00
Summary
Small arteries, while acutely responding to their environment with changes in diameter to regulate local blood flow and pressure, also undergo structural adaptation or remodelling. These events occur over a range of time-frames and involve both non-genetically and genetically regulated events. Thus a contractile event, while initially decreasing vessel diameter, also activates longer time frame processes which can span from rearrangment of cellular junctions-contacts to overt structural changes ....Small arteries, while acutely responding to their environment with changes in diameter to regulate local blood flow and pressure, also undergo structural adaptation or remodelling. These events occur over a range of time-frames and involve both non-genetically and genetically regulated events. Thus a contractile event, while initially decreasing vessel diameter, also activates longer time frame processes which can span from rearrangment of cellular junctions-contacts to overt structural changes within the vessel wall (for example thickening of the muscle layer). These adaptive processes may enable the forces of contraction to be maintained without continued energy expenditure and damage to the vessel per se. However, they can also contribute to long-term alterations in the control of blood pressure and perhaps contribute to states of hypertension as well as other common vascular diseases. For these studies we will use arterioles, isolated by microsurgical techniques, together with sophisticated computer and video-based approaches. These techniques allow arterioles to be studied under controlled conditions and relevant biochemical measurements performed. We will also use a cell model where cultured cells will be studied after defined periods of mechanical stimulation (for example stretch). Cells will be probed using a novel microscopic technique (atomic force microscopy) which enables the cell membrane to be studied with respect to changes in composition as well as physical characteristics (for example stiffness). The studies are relevant to our understanding of the normal adaptive processes occurring within blood vessels to control blood flow and pressure. The studies are also of direct relevance to our understanding of common vascular disease states including hypertension, complications of diabetes and chronic inflammatory disorders.Read moreRead less
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
Developing And Testing Pro-thrombotic Conjugates For Brain AVMs
Funder
National Health and Medical Research Council
Funding Amount
$520,256.00
Summary
Rupture of brain blood vessel abnormalities causes stroke in children and young adults. In this project, we will test new methods for occluding abnormal vessels. We use radiation first to induce changes in the vessels, and then target those changes to occlude the vessels. Successful treatment requires combining targeting and clot forming agents. In this project we will test combinations of targeting and clotting agents. The most effective combination will be progressed towards clinical trials.
An Extended Follow-up Of Stroke Patients For Cognitive Impairment And Neuropsychiatric Disorders: Sydney Stroke Study
Funder
National Health and Medical Research Council
Funding Amount
$321,800.00
Summary
Vascular Dementia (VaD) is the second most common cause of dementia after Alzheimer's disease. In fact, it may be a preventable cause of dementia. Yet it has been relatively neglected by researchers until the last decade, which has seen an upsurge of interest in this disorder. There is no consensus on the criteria for dementia. The profile of early cognitive impairment due to vascular factors is still poorly understood, and the longitudinal course of VaD as defined by modern criteria has not bee ....Vascular Dementia (VaD) is the second most common cause of dementia after Alzheimer's disease. In fact, it may be a preventable cause of dementia. Yet it has been relatively neglected by researchers until the last decade, which has seen an upsurge of interest in this disorder. There is no consensus on the criteria for dementia. The profile of early cognitive impairment due to vascular factors is still poorly understood, and the longitudinal course of VaD as defined by modern criteria has not been studied. There have been few studies of the progressive changes in MRI in patients with cerebrovascular disease. The overlap of VaD and Alzheimer's disease (AD) remains a problem for taxonomists and clinicians. One approach to the study of VaD is to examine a high risk group of subjects longitudinally to determine the early features, the risk factors and progressive changes. With this in mind, we began studying a cohort of stroke patients who are at high risk of VaD, in 1997-1999, and are following them longitudinally. The follow-up is now in its third year, and three neuropsychological assessments and two MRI-MRS scans have been performed. We propose to extend the follow-up to 5 years, with repeat neuropsychiatric, neuropsychological and MRI-MRS investigations, and wherever possible to necropsy, to determine the nature of vascular pathology that underlies cognitive impairment. Our cohort of stroke patients is arguably the most comprehensively assessed such cohorts internationally, and presents an excellent opportunity for a long-term follow-up study.Read moreRead less
The Role Of Dysregulated VEGFs In Lymphatic And Non-lymphatic Vascular Malformations
Funder
National Health and Medical Research Council
Funding Amount
$389,486.00
Summary
Vascular malformations are abnormal growths of blood vessels that affect hundreds of children born in Australia every year. They range from small birthmarks to large destructive growths that cause chronic pain, bleeding and major deformity. This is the largest ever study to systematically look for the biological drivers that cause these growths so that drug treatments will ultimately be able to replace surgery as the first line treatment.
Characterisation Of MiRNAs That Regulate Vascular Leakage.
Funder
National Health and Medical Research Council
Funding Amount
$167,493.00
Summary
Vascular permeability or leak is a major problem in diseases such as cancer and in cardiovascular diseases . MicroRNAs (miRNAs) are small control genes that influence dveleopment and disease. We have identified a miRNA cluster in endothelial cells, the cells that line the blood vessels, that is important in the control of vascular leak. This project is focused on understanding the impact of these miRNAs in disease.
Is Stroke Neurodegenerative? A Longitudinal Study Of Changes In Brain Volume And Cognition Following Stroke
Funder
National Health and Medical Research Council
Funding Amount
$1,044,837.00
Summary
There is no direct evidence linking Alzheimer’s Disease (AD) and stroke. It is unknown whether stroke can trigger progressive dementia in the same way as AD. In a group of stroke patients, we will measure MRI brain volume and cognition in the 5 years after stroke. These findings will be critical for identification of those patients most at risk of dementia after stroke. This will allow future early intervention for these patients, via promising AD disease-modifying therapies.
Does Adenotonsillectomy Change Vascular Function In Children With Sleep Breathing Disorders?
Funder
National Health and Medical Research Council
Funding Amount
$522,105.00
Summary
Sleep breathing disorders affect 10% of all children and when severe, obstruction in the upper airways causes serious deficits in growth, development, brain function and heart health. But even mild snoring (without obstruction) may also cause poor health in the arteries that supply blood to the brain and heart, as well as the smaller arteries in the arms and legs. In both adults and children with conditions like diabetes and obesity, poor blood vessel health has been shown to greatly increase th ....Sleep breathing disorders affect 10% of all children and when severe, obstruction in the upper airways causes serious deficits in growth, development, brain function and heart health. But even mild snoring (without obstruction) may also cause poor health in the arteries that supply blood to the brain and heart, as well as the smaller arteries in the arms and legs. In both adults and children with conditions like diabetes and obesity, poor blood vessel health has been shown to greatly increase the future risk of heart attacks, angina and strokes. Children with severe sleep breathing disorders (such as sleep apnoea syndrome) are currently treated by removal of the tonsils and adenoids, which typically resolves snoring and improves sleep, but it is not yet known whether there are any benefits for blood vessel health. The earliest signs of blood vessel disease in children are abnormal function of the lining of the blood vessels (endothelial dysfunction) and thickening of the lining of blood vessels (intima media thickness). They precede the adult diseases of atherosclerosis - which causes heart attacks and strokes, and diabetic kidney and eye disease. These changes can be measured accurately and non-invasively using ultrasound imaging of arteries in the neck and arm. Our primary aim is to assess whether changes in blood vessel health occur in children with sleep breathing disorders across the range of severity, with a secondary aim to measure any changes in cardiovascular control during both sleep (when snoring occurs). Most importantly, by assessing children before and after surgery, we will be able to see for the first time whether treatment of childhood snoring improves blood vessel health. This study may have major implications for the clinical management of snoring children, who may require treatment at an earlier age to prevent poor blood vessel health and an increased risk of cardiovascular diseases later in life.Read moreRead less