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
Developing Improved Management For Peripheral Artery Diseases
Funder
National Health and Medical Research Council
Funding Amount
$569,219.00
Summary
~1 million Australians have peripheral artery disease. The current application is for a Practitioner Fellowship to support my research aimed at improving care of artery disease. The aim of the work is to develop improved management approaches for patients with blocked and weakened arteries. This work is particularly important given the recognised management deficiencies for patients with artery disease and the relative little research being undertaken in this area.
Ankle Brachial Index Determination By Oscillometric Method IN General Practice (ABIDING)
Funder
National Health and Medical Research Council
Funding Amount
$128,935.00
Summary
People who have peripheral arterial disease (PAD) have blockages of the circulation to their legs. If you have PAD you have blood vessel disease throughout the body and are very likely to have a heart attack or experience a stroke. PAD can be diagnosed simply by comparing the blood pressure in the arms and legs. Until now this needed a special costly instrument. New blood pressure machines can do this without this instrument. We want to know how reliably this can be done by practice nurses.
The Effect Of Stress/strain And Fatigue Fracture Sites On Durability Of Modular Aortic Endografts And Arterial Walls
Funder
National Health and Medical Research Council
Funding Amount
$300,919.00
Summary
Aneurysmal disease is an age related phenomenon. The mean life expectancy of western populations has doubled in 100 years because of the reduction in deaths from preventable and treatable diseases, and prolongation of life with chronic and incurable diseases. The older community (>65 years) continues to be active and productive contrary to prior predictions. Aneurysmal disease has emerged as a result of the changing pattern of diseases in the community. As with many other diseases, prophylaxi ....Aneurysmal disease is an age related phenomenon. The mean life expectancy of western populations has doubled in 100 years because of the reduction in deaths from preventable and treatable diseases, and prolongation of life with chronic and incurable diseases. The older community (>65 years) continues to be active and productive contrary to prior predictions. Aneurysmal disease has emerged as a result of the changing pattern of diseases in the community. As with many other diseases, prophylaxis against aneurysmal disease is the most effective approach since 80% of those that rupture will result in death. Endoluminal grafting provides a much less invasive procedure and provides an attractive and elegant alternative to open surgery. The danger is that structural strengths will be compromised with failures due to lack of strength and inadequate device durability. The most practical endografts are those that are built up from modules but vulnerable sites affected by fatiguing and disruptive forces are being identified, in particular where a tube divides into two outflow channels – the bifurcation - and joins. To improve and protect the current device, and enable sound engineering for future devices, we need to know the nature, magnitude and location of these forces. The existing collaboration with medical specialist, Cook Aust., the Advanced Fluid Dynamics Laboratory (CSIRO, Melb.) and University of WA combines a multidisciplinary team working towards the design and durability of the next generation of endoluminal devices and percutaneous insertions. While Australia is at the forefront of development, its current place in the market can only be maintained by further product development. Optimising and improving endoluminal grafts will reduce the suffering of major surgery while prolonging a higher quality of life with a much less invasive procedure whose long-term effectiveness, and thereby acceptance is dependent upon reliable durability.Read moreRead less
Neurotransmission In Functionally Distinct Vasodilator Pathways
Funder
National Health and Medical Research Council
Funding Amount
$809,934.00
Summary
A surprising feature of our body is that there is not enough blood to fully supply all our organs at once. This is why we sometimes faint when we are hot or get cramps when we are exercising. Consequently, the blood vessels change their diameter so that blood can be directed to the organs with greatest demand at any particular time. For example, if the vessel decreases in diameter, less blood flows through it, but if it increases in diameter, more blood flows through it to reach the appropriate ....A surprising feature of our body is that there is not enough blood to fully supply all our organs at once. This is why we sometimes faint when we are hot or get cramps when we are exercising. Consequently, the blood vessels change their diameter so that blood can be directed to the organs with greatest demand at any particular time. For example, if the vessel decreases in diameter, less blood flows through it, but if it increases in diameter, more blood flows through it to reach the appropriate organ. An important function of the nervous system is to control the flow of blood to different organs by changing the diameters of the blood vessels. One set of nerves decreases the diameter of the arteries, and another set of nerves increases the diameter. The nerves do this by releasing special combinations of chemicals when they get a message from the brain to do so. In this project we are especially interested in the nerves which increase blood flow to organs in the head and the pelvis. We will use a wide range of modern methods to find out how these nerves work. In some experiments, we will use sophisticated electrical equipment to measure just how the nerve cells controlling the diameter of the vessels respond to the instructions sent by the brain. In other experiments, we will find out which chemicals the nerves use to make the blood vessels increase in diameter. We also will discover how the various chemicals get released by the nerves at the right times, so that messages from the brain get to the blood vessels as efficiently as possible. One of the special parts of our project is that we will be able to observe directly the connections between the nerve cells and the blood vessels we are studying. Our results will be important for designing new drugs that could help people whose nerves are not working properly, such as in some patients with diabetes or vascular disease.Read moreRead less
Atherosclerosis: Molecular Mechanisms Of Suppression By CD4+CD25+ Regulatory T-cells
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
Atherosclerosis, or hardening of large arteries is the underlying cause of up to 50% of deaths in Western communities, primarily from heart attacks and strokes. Today it is considered a chronic inflammatory disease arising from the accumulation of fats such as cholesterol into the inner lining of blood vessels including those supply vital organs such as the heart and brain. This study focuses on understanding how to use the body's own anti-inflammatory cells suppress inflammation.
Atherosclerosis: Molecular Action And Suppression Of NKT Cell Subsets
Funder
National Health and Medical Research Council
Funding Amount
$458,815.00
Summary
Atherosclerosis, or hardening of large arteries, is the underlying cause of up to 50% of deaths in Western communities from heart attacks and strokes. Today it is considered a chronic inflammatory disease arising from the influx of fats such as cholesterol into the inner liming of arteries that provide blood supply to organs such as the heart and the brain. However, the exact role that inflammation plays in the development of this blood vessel disease is poorly understood. This study is directed ....Atherosclerosis, or hardening of large arteries, is the underlying cause of up to 50% of deaths in Western communities from heart attacks and strokes. Today it is considered a chronic inflammatory disease arising from the influx of fats such as cholesterol into the inner liming of arteries that provide blood supply to organs such as the heart and the brain. However, the exact role that inflammation plays in the development of this blood vessel disease is poorly understood. This study is directed towards understanding the role of a subset of while blood cells known as NKT cells in the inflammatory process. In particular we will examine whether the activity of NKT cells in promoting atherosclerosis can be controlled either by the administration of drugs that deprive them of molecules that stimulate their activity and-or by the injection of another population of white blood cells known as regulatory T cells that may to limit their activity. Our preclinical study of atherosclerosis in mice has potential for extension to the control of atherosclerosis in humans. Successful translation in this way can be expected to provide a significant health benefit.Read moreRead less
Randomised Trial Of Continuity Of Nursing Care In Vascular Surgery
Funder
National Health and Medical Research Council
Funding Amount
$190,648.00
Summary
Both overseas (Bruni, Hoosier-Paty and Hoffman 1996) and in Australia (Norman, Semmens, Laurence-Brown and Holman, under review), surgeons have become increasingly aware of the need to improve outcomes for patients undergoing arterial surgery for the lower limb. Unlike other areas of health care reform such as cardiac surgery or breast cancer, there is little confidence that the current links between acute facilities, community-based health services and general practice, work optimally together. ....Both overseas (Bruni, Hoosier-Paty and Hoffman 1996) and in Australia (Norman, Semmens, Laurence-Brown and Holman, under review), surgeons have become increasingly aware of the need to improve outcomes for patients undergoing arterial surgery for the lower limb. Unlike other areas of health care reform such as cardiac surgery or breast cancer, there is little confidence that the current links between acute facilities, community-based health services and general practice, work optimally together. Peripheral vascular disease is rarely studied. In NSW, there are about 4200 inpatient episodes for arterial surgery for ischaemia of the lower limb each year (AN-DRG 228 - 232), the majority involving older men. This study brings together a multi-disciplinary team of CIs comprising an academic nurse, two vascular surgeons and an expert in outcomes evaluation to conduct a randomised trial (n-586) of continuity of nursing care for patients admitted for arterial surgery of the lower limb. The intervention is comprised of a 'Patient Stay' Flowchart, continuing postoperative in-patient nursing assessment and staff consultation, Patient Education Discharge Booklet, Patient - Family Care Plan; proactive and reactive telephone follow-up and extensive GP liaison. Blinded outcome evaluation at six and twelve months will compare its differential effectiveness against usual care to which only the Patient Stay' Flowchart has been added. We will generate Level 2 evidence for the effectiveness of continuity of nursing care in improving outcomes for patients undergoing arterial surgery for ischaemia of the lower limb. To our knowledge, this would be the first Australian efficacy trial of its type.Read moreRead less
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
Mechanisms Underlying Disordered Skin Blood Flow Following Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$408,000.00
Summary
Many people who recover from traumatic injury or who have chronic conditions such as diabetes or neuropathy from exposure to a toxic chemical suffer from peripheral vascular disorders leading to poor circulation in the extremities. These conditions are characterised by impaired wound healing, cold hands and feet and ongoing pain. These people must face a long life with progressively increasing disability. Even normal ageing can lead to similar problems. This project is directed at understanding ....Many people who recover from traumatic injury or who have chronic conditions such as diabetes or neuropathy from exposure to a toxic chemical suffer from peripheral vascular disorders leading to poor circulation in the extremities. These conditions are characterised by impaired wound healing, cold hands and feet and ongoing pain. These people must face a long life with progressively increasing disability. Even normal ageing can lead to similar problems. This project is directed at understanding the role of the nerve supply to blood vessels in the skin in these disorders. The experiments will be conducted in skin blood vessels of rats with various forms of nerve lesion that will mimic these conditions in patients. We will use our knowledge of the structure and behaviour of nerve-blood vessel connections to analyse the changes in the properties of vascular smooth muscle and relate it to the state of the innervation. Skin arteries normally receive two types of nerve - sympathetic (which release noradrenaline) and afferent ( which release peptides) - that have opposing actions on the vessel (constriction and dilation respectively). We hypothesize that removal of part or all of the innervation changes the contractile mechanism of the smooth muscle in the wall of the vessel so that it becomes much more sensitive to calcium ions and produces larger and more prolonged contractions. We will combine electrophysiology and contraction studies with immunohistochemistry and biochemical analysis to define the relation between the nerve deficit and the vascular responses. The aim is to identify appropriate drug targets for which local application in the affected region can alleviate the symptoms without causing widespread side effects.Read moreRead less