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
Preclinical In Vivo Evaluation Of SFLT Secretion Gene Therapy For Retinal And Choroidal Neovascularisation
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
The aim of this project is to develop a long-term treatment for diabetes-related retinal neovascularisation, reduce the occurrence of diabetic macular oedema and provide a highly effective treatment for age-related macular degeneration related choroidal neovascularisation before vision loss. The proposed technique would potentially be a major advance in disease management by providing a significantly improved or complementary treatment to the current therapies of laser photocoagulation, vitrecto ....The aim of this project is to develop a long-term treatment for diabetes-related retinal neovascularisation, reduce the occurrence of diabetic macular oedema and provide a highly effective treatment for age-related macular degeneration related choroidal neovascularisation before vision loss. The proposed technique would potentially be a major advance in disease management by providing a significantly improved or complementary treatment to the current therapies of laser photocoagulation, vitrectomy and photodynamic therapy. The proposed strategy utilizes recombinant virus-mediated gene delivery which basically produces the therapeutic agent specifically at the location of the disease. These studies addressing the feasibility of secretion gene therapy (SGT) will be readily applicable to our Gene Discovery Program Grant (JDRF-NHMRC 219166) that is set out to identify new anti-angiogenic genes.Read moreRead less
Cellular And Molecular Mechanisms Of Human Choroidal And Retinal Vascularisation
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
The abnormal growth of new blood vessels is a major cause of blindness in people of all ages. In premature infants, changes in retinal blood vessels results in Retinopathy of Prematurity (ROP) the leading cause of infant blindness in the world. In older adults with age-related macular degeneration (ARMD), vessels in the choroid can grow into and under the retina where they can cause catastrophic loss of vision. This association of abnormal vessel growth with the most common causes of blindness h ....The abnormal growth of new blood vessels is a major cause of blindness in people of all ages. In premature infants, changes in retinal blood vessels results in Retinopathy of Prematurity (ROP) the leading cause of infant blindness in the world. In older adults with age-related macular degeneration (ARMD), vessels in the choroid can grow into and under the retina where they can cause catastrophic loss of vision. This association of abnormal vessel growth with the most common causes of blindness has motivated the search for a better understanding of how blood vessel growth in the eye is controlled in healthy tissues and how these controls fail in disease. Our proposal addresses this issue directly. Recent work shows that this neovascularization is not only a response to a rise in the local concentration of molecules that induce such angiogenesis, but also requires a fall in the levels of endogenous molecules that inhibit angiogenesis. Our study will investigate the expression of newly identified angiogenic growth factors (VEGFs) and their receptors as well as angiogenic inhibitors (VEGI and PEDF) in the developing and adult human retina and choroid. We will examine the mechanisms by which the human choroid is formed. Our preliminary results suggests the novel insight that vasculogenesis (the formation of blood vessels via transformation of vascular precursor cells) plays a major role the formation of both the human retina and choroid. Further, these exciting results suggest involvement of novel growth stimulators and inhibitors previously not known to play a role in these processes. Our studies will lead to new insights regarding the vascular growth factors and inhibitors that drive this process, thus leading to a rational basis for new therapeutic targets for the treatment of ARMD. The rapid aging of the Australian population and the consequent predicted doubling of ARMD incidence in the next 20 years demonstrates the urgency of our studies.Read moreRead less
Characterisation Of MiRNAs That Regulate Vascular Leakage.
Funder
National Health and Medical Research Council
Funding Amount
$167,493.00
Summary
Vascular permeability or leak is a major problem in diseases such as cancer and in cardiovascular diseases . MicroRNAs (miRNAs) are small control genes that influence dveleopment and disease. We have identified a miRNA cluster in endothelial cells, the cells that line the blood vessels, that is important in the control of vascular leak. This project is focused on understanding the impact of these miRNAs in disease.
Role Of Epigenomic Changes In Conferring Hyperglycemic Memory
Funder
National Health and Medical Research Council
Funding Amount
$636,146.00
Summary
The major burden of type I diabetes remains its vascular complications including diabetes-accelerated athersclerosis. Despite improved glucose control, diabetic individuals develop complications as a result of prior poor glycemic control. Although the development and progression of these diabetic complications is strongly associated with mean levels of glucose, recent studies suggest that the deleterious effects of early exposure to high levels of glucose persist for years even after treatment h ....The major burden of type I diabetes remains its vascular complications including diabetes-accelerated athersclerosis. Despite improved glucose control, diabetic individuals develop complications as a result of prior poor glycemic control. Although the development and progression of these diabetic complications is strongly associated with mean levels of glucose, recent studies suggest that the deleterious effects of early exposure to high levels of glucose persist for years even after treatment has returned glucose levels towards normal.Read moreRead less
Calcification of the arteries is a ubiquitous finding in patients with end stage renal failure. It is often mirrored by disturbed bone metabolism. Increasing evidence suggests a close relationship between bone and vascular health. This study aims to determine the role of calciprotein particles as a mediator of calcification in bones and arteries. Translating these findings to renal patients will ultimately contribute to providing a scientific basis for developing treatment for these patients.
Non-Alzheimer Dementia: Pathogenesis And Clinicopathological Correlations
Funder
National Health and Medical Research Council
Funding Amount
$437,036.00
Summary
Dementia affects as many as 20% of people in their eighties. Although much of this is caused by Alzheimer's disease (AD), other types of dementia are also important. In this study we will look at two types of non-Alzheimer dementia, frontotemporal dementia (FTD) and small vessel cerebrovascular disease (SVD). The clinical symptoms of SVD closely resemble AD. Conversely, FTD results in degeneration of those parts of the brain which are responsible for personality, behaviour and language. We will ....Dementia affects as many as 20% of people in their eighties. Although much of this is caused by Alzheimer's disease (AD), other types of dementia are also important. In this study we will look at two types of non-Alzheimer dementia, frontotemporal dementia (FTD) and small vessel cerebrovascular disease (SVD). The clinical symptoms of SVD closely resemble AD. Conversely, FTD results in degeneration of those parts of the brain which are responsible for personality, behaviour and language. We will look at the brains of patients who have died with these diseases and determine the types of neurons which are damaged and their distribution in the brain. We will also investigate whether an individual's genetic make-up influences the development of SVD. In addition, in collaboration with neuropathologists across Australia, we will develop and standardise criteria for the pathological diagnosis of these diseases. Overall, this study will better characterise the pathology of two commonly encountered non-AD dementias and provide valuable insights into their causes.Read moreRead less
Regulation Of Bone Marrow Progenitor Cells For Diabetic Retinopathy
Funder
National Health and Medical Research Council
Funding Amount
$442,930.00
Summary
Diabetic retinopathy (DR) is the leading cause of blindness in the working population of developed countries. Current treatments cannot restore the retinal vascular damage in DR. This project intends to combat DR by repairing the damaged retinal vasculature through short- and long-term regulations of the function of bone marrow derived endothelial progenitor cells. Success in this project would potentially have a major impact on all diabetic vascular complications.
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