The Role Of The Endothelium In Insulin's In Vivo Action Upon Skeletal Muscle Metabolism.
Funder
National Health and Medical Research Council
Funding Amount
$451,500.00
Summary
A number of studies using novel techniques developed in association with our USA collaborators, indicate that insulin has a major stimulatory effect on blood flow within muscle in both animals and humans to improve access for itself as well as nutrients such as glucose. As much as 50% of the glucose taken up by muscle in vivo during continual exposure to insulin may be attributed to this effect. Moreover, this haemodynamic effect of insulin in muscle is impaired in a number of animal models and ....A number of studies using novel techniques developed in association with our USA collaborators, indicate that insulin has a major stimulatory effect on blood flow within muscle in both animals and humans to improve access for itself as well as nutrients such as glucose. As much as 50% of the glucose taken up by muscle in vivo during continual exposure to insulin may be attributed to this effect. Moreover, this haemodynamic effect of insulin in muscle is impaired in a number of animal models and in obese humans when insulin mediated muscle glucose uptake is also impaired. What is not known is how insulin mediates this haemodynamic effect of recruiting capillary blood flow. Thus in the present study a number of aspects are to be explored, with particular focus on the cells that line the blood vessels and constitute the capillaries, the so called endothelium. First, we will explore the specific role of the endothelium in insulin's action by using the novel approach of attaching insulin to a large molecule that prevents it leaving the lumen of the blood vessel. This will mean that insulin will be confined to interacting only with insulin receptors on the muscle endothelium. Similarly, non activating anti insulin receptor antibody will be used in the presence of insulin to selectively prevent activation of the endothelial insulin receptors. In addition, we will investigate whether homocysteine, an amino acid found to impair endothelial dependent vasodilatation, impairs the haemodynamic effects of insulin. The impact that normal insulin release after a meal has upon the haemodynamic actions in muscle and the role this has in muscle glucose uptake will also be investigated by using the techniques developed in the first part of the project. Our over riding hypothesis is that the endothelium plays a key role in controlling insulin and possibly glucose access to muscle cells and thus a significant proportion of insulin mediated metabolic events in muscle.Read moreRead less
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
Astrocytes And Mural Cells In The Retina: Normal Development And Pathophysiology
Funder
National Health and Medical Research Council
Funding Amount
$679,616.00
Summary
The blood vessels that supply the nerve cells of the brain and retina are associated with support cells known as mural cells and astrocytes. Whereas astrocytes both ensure that the vessels do not leak and produce factors that induce vessel growth, mural cells control blood flow and are thought to promote vessel stability. We aim to characterise the development of astrocytes and mural cells as well as the interactions of these cells with blood vessels that influence vessel shape, growth, and loss ....The blood vessels that supply the nerve cells of the brain and retina are associated with support cells known as mural cells and astrocytes. Whereas astrocytes both ensure that the vessels do not leak and produce factors that induce vessel growth, mural cells control blood flow and are thought to promote vessel stability. We aim to characterise the development of astrocytes and mural cells as well as the interactions of these cells with blood vessels that influence vessel shape, growth, and loss. Aging is associated with changes in the vasculature of the central nervous system that confer a predisposition to certain conditions, such as dementia, caused by abnormal blood supply and consequent nerve cell death. We plan to investigate the contribution of astrocytes and mural cells to the vascular changes that accompany aging. These studies may lead to the development of interventions to prevent such changes and their associated pathologies. Finally, astrocyte degeneration is implicated in various neuropathological conditions, including dementia, Alzheimer's disease, and trauma. We aim to purify and characterise a population of astrocyte precursor cells whose transplantation might result in the repopulation of damaged regions of the central nervous system.Read moreRead less
Acute pancreatitis is an acute abdominal inflammatory process (the pancreas attempts to digest itself) with significant mortality in those patients having the severe form of the disease. The commonest causes of the disease are gallstones and excessive alcohol consumption. Approximately 80% of patients with acute pancreatitis recover, but 20% experience the severe form of the disease. In severe pancreatitis, 30% of patients die. Severe pancreatitis is associated with necrosis (cell death) of the ....Acute pancreatitis is an acute abdominal inflammatory process (the pancreas attempts to digest itself) with significant mortality in those patients having the severe form of the disease. The commonest causes of the disease are gallstones and excessive alcohol consumption. Approximately 80% of patients with acute pancreatitis recover, but 20% experience the severe form of the disease. In severe pancreatitis, 30% of patients die. Severe pancreatitis is associated with necrosis (cell death) of the pancreas which, results from reduced blood flow in the organ. This reduced blood flow may be secondary to increased pressure in the pancreatic duct following occlusion of the duct. Preliminary studies suggest that the reason why the pancreas may be susceptible to necrosis is the anatomical arrangement of its blood supply, being made up of many end arterioles (very small arteries) that do not connect with other arteries. The consequence of this arrangement is that if a particular end arteriole becomes blocked, the area of the tissue cannot obtain a blood supply from neighbouring arterioles (as in other organs). Blood supply is partly controlled by nerves. The nerve transmitter nitric oxide is one of the major chemicals involved in this regulation. Nitric oxide also regulates the pressure in the pancreatic duct by acting on the sphincter of Oddi, situated at the opening of the pancreatic duct. Consequently, the action of nitric oxide during pancreatitis may be crucial to the development of the severe disease. This proposal seeks to define the blood supply of the pancreas, its regulation, the effect that increased pancreatic duct pressure has on it and the role that nitric oxide plays in this. If the hypotheses regarding the role of nitric oxide on pancreatic blood flow is proven, then drugs which influence nitric oxide levels can be used to limit the production of pancreatic necrosis. In turn, such an effect will reduce the mortality and morbidity of acute pancreatitis.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