Interaction Of Angiotensin II And PPARg In Aortic Aneurysm Formation
Funder
National Health and Medical Research Council
Funding Amount
$427,398.00
Summary
Between 5% to 10% of men and 1% of women over the age of 60 years develop weakening of their main abdominal artery leading to slow dilation of the vessel. If this process continues long term the artery can burst resulting in sudden death. At present the only treatment available for this problem is surgery, either open or minimally invasive. Both these forms of treatment are associated with significant complications and unsuitable for some patients. Thus the development of a drug treatment which ....Between 5% to 10% of men and 1% of women over the age of 60 years develop weakening of their main abdominal artery leading to slow dilation of the vessel. If this process continues long term the artery can burst resulting in sudden death. At present the only treatment available for this problem is surgery, either open or minimally invasive. Both these forms of treatment are associated with significant complications and unsuitable for some patients. Thus the development of a drug treatment which can slow or halt the weakening and dilation of the aorta would have great patient benefits. We have identified an important role for a newly discovered protein in weakening of the abdominal aorta. In this study we investigate the role of a pathway which appears to be fundamental in generating this protein. In particular we will assess the role of drug treatment in blocking this pathway as a basis for medical treatment for artery weakening.Read moreRead less
Role Of Osteoprotegerin In Protecting The Diabetic Aorta From Aneurysm Formation
Funder
National Health and Medical Research Council
Funding Amount
$299,250.00
Summary
Between 5% and 10% of men over the age of 60 years develop weakening of their main abdominal artery (aorta) leading to slow dilation of the vessel. If this process continues long term the artery can burst resulting in sudden death. At present the only treatment available for this problem is surgery, either open or minimally invasive. Both these forms of treatment are associated with significant complications and unsuitable for some patients. Thus the development of a drug treatment which can slo ....Between 5% and 10% of men over the age of 60 years develop weakening of their main abdominal artery (aorta) leading to slow dilation of the vessel. If this process continues long term the artery can burst resulting in sudden death. At present the only treatment available for this problem is surgery, either open or minimally invasive. Both these forms of treatment are associated with significant complications and unsuitable for some patients. Thus the development of a drug treatment which can slow or halt the weakening and dilation of the aorta would have great patient benefits'. Surprisingly patients with sugar diabetes are less likely to develop this form of artery weakening. This important negative association may form the basis of discovering a new medication to protect arteries from rupture. In this study we investigate the role of a recently discovered protein in protecting the main abdominal artery from weakening in diabetics. This protein is of particular interest for the following reasons: 1. It comes from a group of proteins believed to be important in artery calcium build-up. 2. Artery calcium is common in patients with diabetes who are relatively protected from aortic weakening. 3. It is being used for the treatment of bone weakening, appears to be safe in patients and therefore is a potential therapeutic agent. We believe this work is an important step towards the development of a successful medical treatment for artery weakening.Read moreRead less
Optimising Islet Transplantation With Vascularized Tissue Engineering Chambers
Funder
National Health and Medical Research Council
Funding Amount
$451,651.00
Summary
Diabetics have high blood sugar levels because cells in the pancreas known as islets produce too little of the hormone insulin. Most diabetics need daily insulin injections to maintain normal blood sugar levels. Transplanting islets is the most promising way to treat type 1 diabetes, but, apart from the obvious difficulty of rejection of foreign islets, several major problems remain: (1) there are insufficient pancreata (and therefore islets) for transplantation; and (2) the efficiency of delive ....Diabetics have high blood sugar levels because cells in the pancreas known as islets produce too little of the hormone insulin. Most diabetics need daily insulin injections to maintain normal blood sugar levels. Transplanting islets is the most promising way to treat type 1 diabetes, but, apart from the obvious difficulty of rejection of foreign islets, several major problems remain: (1) there are insufficient pancreata (and therefore islets) for transplantation; and (2) the efficiency of delivery of surviving islet transplants is too low. In pilot studies we have grown a new living pancreatic organ in mice by inserting islets from genetically-related mice together with a structural protein matrix, growth factors and blood vessels inside a plastic chamber. The blood vessels maintain nutrition to the islet cells and simultaneously allow insulin to be released into the bloodstream, thus normalising the high blood sugar in diabetics. In Aim 1 of these experiments we will find the optimal way to grow mature islets in blood vessel-containing chambers in diabetic mice, focusing on (a) the best time to add islets to the chamber - 0, 1 or 2 weeks after establishment, (b) the minimum number of islets to effectively normalise blood sugar and (c) how long we can keep islets alive and functional in chambers, examining periods up to 12 months. In Aim 2 we will test the ability of islet stem cells (provided by our co-investigators at Walter and Eliza Hall Institute, Melbourne) to survive in the chambers and to produce sufficient insulin to effectively lower blood sugar levels to normal in diabetic mice. In Aim 3 we will grow human islets in chambers in special diabetic mice that do not reject foreign tissue, in order to confirm similar behaviour of human islets in this controlled environment. Using this data, we hope to create a research model of functioning islets, that is accessible, retrievable and manipulable, for the further study of diabetes and transplantation.Read moreRead less
Susceptibility To Venous Leg Ulceration: Investigation Of The First Genetic Risk Factor
Funder
National Health and Medical Research Council
Funding Amount
$291,000.00
Summary
This application aims to confirm our preliminary identification of the first candidate gene as a risk factor for developing venous leg ulceration. Since patients with venous leg ulcers experience pain and psychological consequences including anger and depression, all of which impact negatively on quality of life, active prevention of ulceration will have significant lifestyle and financial benefits. Venous leg ulcers occur in patients who have venous disease, in particular in patients with previ ....This application aims to confirm our preliminary identification of the first candidate gene as a risk factor for developing venous leg ulceration. Since patients with venous leg ulcers experience pain and psychological consequences including anger and depression, all of which impact negatively on quality of life, active prevention of ulceration will have significant lifestyle and financial benefits. Venous leg ulcers occur in patients who have venous disease, in particular in patients with previous deep vein thrombosis. However, not all patients with a deep vein thrombosis or other forms of venous disease will go on to develop a venous ulcer. Our preliminary results show that patients with a venous ulcer have a greater frequency of this gene than healthy controls without venous ulcers, and suggest that patients with the candidate gene have a greater risk of developing venous ulceration. In this study we aim to determine whether the gene itself contributes to ulcer susceptibility or whether it is just a marker of that susceptibility. We can do this by assessing related genes and the levels of the protein produced by this gene. In this study we also aim to assess whether patients with a proven deep vein thrombosis are more likely to develop venous ulceration if they have the candidate gene. These studies have the potential to lead to the development of a diagnostic screening test for use in patients with venous disease, to assess the likelihood of developing leg ulceration. This will enable more active treatment to prevent leg ulceration. If this gene contributes to ulcer susceptibility new specific treatments may be developed for ulcer management and prevention.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