Understanding The Role Of Cell Death In Blood Vessel Regression And Regrowth
Funder
National Health and Medical Research Council
Funding Amount
$468,059.00
Summary
Blood vessels are essential to distribute oxygen and nutrients throughout our bodies, and as such, disruptions to normal blood vessel behaviour can have significant impacts on health. This research is aimed at understanding how blood vessel networks can regrow after damage in order to maintain healthy blood supply to a tissue. This work will be particularly relevant to diseases where blood vessel loss or inappropriate blood vessel growth occur.
How Is Lipoprotein Disposition Influenced By Fenestrae In The Hepatic Sinusoidal Endothelium?
Funder
National Health and Medical Research Council
Funding Amount
$310,500.00
Summary
Understanding lipoprotein metabolism is critical for the prevention of vascular disease. The liver is the main site for lipoprotein metabolism. The initial step in the metabolism of lipoproteins by the liver is their transfer across the liver sinusoidal endothelial cells from the blood to the liver cells. Sinusoidal endothelial cells contain pores called fenestrae that are thought to allow direct passage of large substances and thus filter lipoproteins on the basis of size. We propose to fully d ....Understanding lipoprotein metabolism is critical for the prevention of vascular disease. The liver is the main site for lipoprotein metabolism. The initial step in the metabolism of lipoproteins by the liver is their transfer across the liver sinusoidal endothelial cells from the blood to the liver cells. Sinusoidal endothelial cells contain pores called fenestrae that are thought to allow direct passage of large substances and thus filter lipoproteins on the basis of size. We propose to fully define the role of fenestrae in the ultrafiltration of particles such as lipoproteins and microspheres. This will confirm that ultrafiltration by fenestrae in the liver endothelium is an important biological process akin to filtration by the kidney, and relevant for lipoprotein metabolism. We will determine whether oxidative stress, which generates large gaps in the sinusoidal endothelium, increases the transfer of lipoproteins into the liver. This provides a novel mechanism for fatty liver that follows toxic liver injury, and hence, a therapeutic target for this condition. We will determine whether loss of fenestrae induced by the synthetic non-ionic surfactant, pluronic 407, reduces transfer of lipoproteins. This is an entirely novel mechanism and risk factor for hyperlipidaemia. Finally we will investigate lipoprotein (a) which is a potent risk factor for vascular disease. We will assess with lipoprotein (a), through binding other lipoproteins and increasing their size, impedes their transfer through the fenestrations for subsequent hepatic metabolism. From the basic perspective, these studies will prove that fenestrations in the liver endothelial cell are an ultrafiltration system that is significant for lipoprotein metabolism. From the clinical perspective, the studies will generate novel mechanisms for impaired hepatic metabolism of lipoproteins as well as indicating that fenestrae are a potential target for the development of lipid-lowering pharmacotherapies.Read moreRead less
Normal organ development and many disease processes, such as cancer and tissue damage, depend upon formation of new blood vessels. Our research seeks to identify novel factors regulating blood vessel growth. In this context we have examined the role of proteins that mediate communication between cells, called connexins. By increasing our understanding of the factors affecting blood vessel growth we learn how to create novel therapies to enhance the treatment of ischemic disease and cancer.
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.
Relationship Between Cell-cell Interactions And Disease Severity In Patients With Cerebral Malaria
Funder
National Health and Medical Research Council
Funding Amount
$545,183.00
Summary
Severe malaria is a collection of disease complications that leads to about 2 million deaths each year worldwide. Young children in Africa and young adults in several parts of South-East Asia are particularly affected. Travellers to these regions are also at considerable risk. One of the most dangerous complications of malaria is when the brain becomes affected, which is called cerebral malaria. We still do not understand enough about the changes that link the parasite circulating in the blood w ....Severe malaria is a collection of disease complications that leads to about 2 million deaths each year worldwide. Young children in Africa and young adults in several parts of South-East Asia are particularly affected. Travellers to these regions are also at considerable risk. One of the most dangerous complications of malaria is when the brain becomes affected, which is called cerebral malaria. We still do not understand enough about the changes that link the parasite circulating in the blood with the devastating disturbance of brain function that causes death in some people who develop cerebral malaria. In this project we will investigate some new ideas about how cerebral malaria develops. We will perform a detailed study of brain tissue taken from victims of cerebral malaria and compare the observations with similar ones in children who died of other causes. Then we will work with an experimental model we have developed, in which we put together in culture flasks the various types of cell that are found in the brain lesions in people who die from cerebral malaria. Our aim is to identify some new therapeutic targets for later use in treatment of cerebral malaria patients.Read moreRead less
Endothelial Development From Pluripotent Stem Cells As A Means To Study Pathology In Pulmonary Artery Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$613,311.00
Summary
Pulmonary artery hypertension (PAH) is a fatal disease primarily affecting young adults. It is caused by a defect in cells that form the vessel that carries blood from the heart to the lungs. We will use stem cells made from the skin of PAH patients to examine why the blood vessel cells from these patients fail to function normally.
Thromboxane Receptor Signaling In Endothelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$584,985.00
Summary
Normal organ development and many disease processes, such as cancer and ischemia, depend upon formation of new blood vessels. Our research seeks to identify novel factors regulating blood vessel growth. In this context we have examined the role of short lived lipid derivatives, called eicosanoids. By increasing our understanding of the factors affecting blood vessel growth we learn how to create novel therapies to enhance the treatment of ischemic disease and cancer.