Epigenetic Reprogramming Of Calcified Vascular Smooth Muscle Cells As A Treatment For Vascular Calcification
Funder
National Health and Medical Research Council
Funding Amount
$1,285,195.00
Summary
Pathological hardening of blood vessels, or vascular calcification, is a frequent and deadly complication of many cardiovascular disorders. It is caused by the irreversible change in mature vascular smooth muscle cells (the main cell type in the blood vessel walls) to a bone-forming cell type. We have now identified a new gene that can potentially revert calcified vascular cells back to their physiological state. This represents a promising new approach for treatment of vascular calcification.
Mechanisms Of Vascular Dysfunction During Acute And Chronic Hyperglycemia
Funder
National Health and Medical Research Council
Funding Amount
$56,700.00
Summary
Increased consumption of sugary drinks has contributed to an epidemic of obesity and diabetes and consequently cardiovascular disease. For the first time in living memory, this may well lead to declining life-expectancy. My research will examine both the short and long-term impact of sugary drinks on vital blood vessel function. In the process it will develop better methods to monitor blood vessel function and inform public health policy on sugary drinks and preventing cardiovascular disease.
The Role Of The MicroRNA Let 7 In Diabetic Proliferative Vascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$674,084.00
Summary
Cardiovascular complications remain the major cause of mortality in diabetes and our current treatment strategies are insufficient to reduce this burden. We have obtained extensive data to show that a novel molecule (the micro RNA, let 7b) has antiproliferative and vasculoprotective effects in diabetes. Thus, we propose that modulation of micro RNA let 7b specifically in vascular smooth muscle cells within the vascular wall represents a promising target to combat cardiovascular disease, in parti ....Cardiovascular complications remain the major cause of mortality in diabetes and our current treatment strategies are insufficient to reduce this burden. We have obtained extensive data to show that a novel molecule (the micro RNA, let 7b) has antiproliferative and vasculoprotective effects in diabetes. Thus, we propose that modulation of micro RNA let 7b specifically in vascular smooth muscle cells within the vascular wall represents a promising target to combat cardiovascular disease, in particular in diabetes.Read moreRead less
The Plasmalemmal Calcium Pump And Vascular Smooth Muscle Cell Proliferation.
Funder
National Health and Medical Research Council
Funding Amount
$179,593.00
Summary
Excessive growth of smooth muscle cells can lead to adverse effects in our arteries. The level of calcium inside the muscle cells that line our arteries appears to regulate their growth. In these studies we will assess the changes in the synthesis (expression) of a pump which removes calcium from cells. We will also characterise the effects of modifiers of cell growth on the expression of the calcium pump. The effect of directly inhibiting the production of the calcium pump, on the growth of smo ....Excessive growth of smooth muscle cells can lead to adverse effects in our arteries. The level of calcium inside the muscle cells that line our arteries appears to regulate their growth. In these studies we will assess the changes in the synthesis (expression) of a pump which removes calcium from cells. We will also characterise the effects of modifiers of cell growth on the expression of the calcium pump. The effect of directly inhibiting the production of the calcium pump, on the growth of smooth muscle cells and the regulation of calcium will be determined for the first time.Read moreRead less
Pathogenesis Of Vascular Shock And Platelet Dysfunction In Sepsis: The Role Of Calcium Desensitization, Statins And Cortisol.
Funder
National Health and Medical Research Council
Funding Amount
$89,778.00
Summary
Severe infections are characterised by a profound drop in blood pressure, which starve vital organs of oxygen and nutrients, this �septic shock� can lead to organ failure and death. We aim to identify dysfunction of the molecular signals in blood vessels, which leads to the failure of these vessels to maintain adequate blood pressure. Understanding the mechanisms regulating blood pressure during septic shock will enable us to develop therapies to support the circulation and reduce the significan ....Severe infections are characterised by a profound drop in blood pressure, which starve vital organs of oxygen and nutrients, this �septic shock� can lead to organ failure and death. We aim to identify dysfunction of the molecular signals in blood vessels, which leads to the failure of these vessels to maintain adequate blood pressure. Understanding the mechanisms regulating blood pressure during septic shock will enable us to develop therapies to support the circulation and reduce the significant death toll from life threatening sepsis.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
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