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
Imaging Neutrophil And Endothelial Function In Acute Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$545,517.00
Summary
The glomerulus is a group of small blood vessels which form the filtering component of the kidney. In many diseases, it can be the target of an inappropriate inflammatory response during which white blood cells accumulate in the glomerular blood vessels and cause damage. In this project, we will visualise the blood vessel lining of the glomerulus in order to understand how white blood cells damage this region and cause leakage of protein leak into the urine.
Modulation Of Endothelial Junctions As Selective Immunotherapy
Funder
National Health and Medical Research Council
Funding Amount
$911,387.00
Summary
We have developed a new drug (CD5-2) that targets the junctions of endothelial cells, the cell that lines all vessels. CD5-2 reduces oedema in diseases such as diabetic retinopathy and tumours. Thus it has potential as a new therapeutic in chronic inflammatory diseases where leaky blood vessels are central to the pathology. This grant will provide fundamental understanding of how CD5-2 induces such profound effects to alter the levels of oedema and alter inflammatory cell infiltrates in tissues.
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.
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.