Peripheral Mechanisms Involved In Autonomic Hyperreflexia
Funder
National Health and Medical Research Council
Funding Amount
$229,917.00
Summary
Bladder distension or minor unheeded injuries below the lesion in spinally injured people often lead to episodes of high blood pressure that may cause stroke or death. These events require emergency hospitalization and are expensive as well as dangerous. After spinal injury, the control of sympathetic nerves that supply arteries and regulate blood pressure is lost. However, the nerves below the injury remain in place and the spinal cord below the lesion contains connections that can activate the ....Bladder distension or minor unheeded injuries below the lesion in spinally injured people often lead to episodes of high blood pressure that may cause stroke or death. These events require emergency hospitalization and are expensive as well as dangerous. After spinal injury, the control of sympathetic nerves that supply arteries and regulate blood pressure is lost. However, the nerves below the injury remain in place and the spinal cord below the lesion contains connections that can activate them. Signals from the bladder or skin enter the remaining lower part of the spinal cord and activate the sympathetic supply generating a rise in blood pressure. This project will test the hypothesis that increased sensitivity of arteries to the chemicals released from the sympathetic nerves leads to excessive vessel constriction, contributing to the exaggerated increase in pressure. We will investigate arteries removed from rats with experimental spinal transection. We will test the contractions of the arteries (a) to sympathetic nerve stimulation and (b) to the chemicals noradrenaline, adenosine 5'-triphosphate (ATP) and neuropeptide Y that are normally released during nerve activity. We will determine whether release of noradrenaline and ATP from nerves is normal or augmented using electrochemical and electrophysiological techniques. We will compare the responses with those in normal arteries, those in arteries whose nerves have been silenced by removing all connections from the spinal cord and those in arteries that have lost all their nerve supply. This will enable us to identify whether the mechanisms for release of transmitter substances are modified and whether the arterial muscle is hypersensitive to these substances. The results will help in the design of safer treatment for these potentially lethal emergencies in spinal patients.Read moreRead less
A Case Control Study Of Hypertension In The Setting Of Poverty, Overcrowding And Infection.
Funder
National Health and Medical Research Council
Funding Amount
$603,331.00
Summary
It is unclear why chronic diseases are emerging in regions of significant disadvantage, i.e. where people are not overweight, are physically active and relatively young. We aim to identify factors responsible for the development of high blood pressure in a region where there is overcrowding, poverty, and infection. Low cost strategies to modify risk and educate the community can then be developed to prevent the emergence of these diseases.
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
How Does Activated Protein C Create Intact, Non-leaky, Stable Blood Vessels?
Funder
National Health and Medical Research Council
Funding Amount
$564,644.00
Summary
Vascular dysfunction is a common feature of many diseases, including sepsis, diabetes, atherosclerosis, tumours and asthma. These vessels have compromised structural and functional integrity, leading to leakage of blood components and causing inflammation in tissues. Based on our recent findings, this project aims to discover how activated protein C creates normal, healthy non-leaky blood vessels and prevents vascular dysfunction in disease.
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
Antioxidant Glutathione Peroxidase (GPx) Mimetics And Atherosclerosis: A Role For Targeted Antioxidant Therapy.
Funder
National Health and Medical Research Council
Funding Amount
$358,319.00
Summary
This proposal investigates the use of antioxidant therapy, targeted at increasing the function of the body's important antioxidant enzyme GPx1, to reduce atherosclerosis both in a non-diabetic and diabetic setting. Strong clinical evidence and our recently published data support an important role for GPx1 in limiting atherosclerosis. We will now investigate the molecular mechanisms involved in mediating these effects and whether compounds that mimic GPx1 function reduce atherosclerosis.
Vascular And Neuro-glial Dysfunction In Diabetic Retinopathy
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
The retina is responsible for sight. Vision occurs by interactions between blood vessels, neurons (cells that transmit electrical signals for vision) and glia (cells that support the retina). In diabetes, high amounts of glucose in blood increases certain factors within retinal cells. These factors slowly cause damage, such that after 15 years of diabetes all patients will have some retinal disease and many will loose sight. Indeed, diabetes is the leading cause of blindness in working people. T ....The retina is responsible for sight. Vision occurs by interactions between blood vessels, neurons (cells that transmit electrical signals for vision) and glia (cells that support the retina). In diabetes, high amounts of glucose in blood increases certain factors within retinal cells. These factors slowly cause damage, such that after 15 years of diabetes all patients will have some retinal disease and many will loose sight. Indeed, diabetes is the leading cause of blindness in working people. The main treatment for diabetic retinal disease is to burn away damaged blood vessels, however, this treatment has problems. Firstly, the burns destroy healthy retina and the disease continues, secondly, the treatment is performed late in the disease and therefore does not prevent the early changes in retinal cells, and thirdly, changes in neurons and glia are often not considered. Therefore, there is an urgent need to understand how blood vessels, neurons and glia interact with each other to threaten vision in diabetes, with the intention of developing safer and more effective treatments. This will be the focus of the current project. Currently, there are no studies that have examined the sequential changes in retinal blood vessels, neurons and glia in diabetes. This is mainly due to the lack of an experimental rodent model that progresses from mild to severe diabetic retinal disease. In 2003, we established such a model in the diabetic Ren-2 rat. In this project the diabetic Ren-2 rat will be used to study retinal cell changes and also to identify the factors that damage these cells. We suggest that angiotensin, bradykinin and VEGF are involved. These factors are present in the normal retina and are increased in diabetes. We will block these factors with specific drugs with the intention of understanding how these factors affect retinal cells in diabetes, and also to develop new drug therapies for the treatment of both early and late diabetic retinal disease.Read moreRead less