Activin A And Follistatin Are Potential Key Regulators Of Organ Transplant Dysfunction And Graft Survival.
Funder
National Health and Medical Research Council
Funding Amount
$535,579.00
Summary
The grant examines novel key regulators in organ transplantation. It examines molecules that are released during transplant surgery and on the return of blood flow to the organ which can cause inflammation and scarring. The release is increased by heparin, an anticoagulant used in organ preparation. Alternative anticoagulants and blockers of the regulators released will be tested to prevent the damage to the transplant, potentially improving both the short and long term graft survival and functi ....The grant examines novel key regulators in organ transplantation. It examines molecules that are released during transplant surgery and on the return of blood flow to the organ which can cause inflammation and scarring. The release is increased by heparin, an anticoagulant used in organ preparation. Alternative anticoagulants and blockers of the regulators released will be tested to prevent the damage to the transplant, potentially improving both the short and long term graft survival and function.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
Clinical Feasibility Study Of Omega-3 PUFA Therapy For The Reduction Of Post-cardiac Surgery Atrial Arrhythmias
Funder
National Health and Medical Research Council
Funding Amount
$442,092.00
Summary
The aim of this study is to determine the molecular and clinical impact of omega-3 polyunsaturated fatty acids (PUFA) pre-treatment 2 weeks before cardiac surgery in 150 patients. The outcome of this proposal will indicate proof of molecular concepts, clinical feasibility and specific design elements of a future, large scale, placebo controlled, prospective randomised trial of oral therapy with omega-3 polyunsaturated fatty acids (PUFA). Recently, omega-3 PUFA via fish diet was reported to be li ....The aim of this study is to determine the molecular and clinical impact of omega-3 polyunsaturated fatty acids (PUFA) pre-treatment 2 weeks before cardiac surgery in 150 patients. The outcome of this proposal will indicate proof of molecular concepts, clinical feasibility and specific design elements of a future, large scale, placebo controlled, prospective randomised trial of oral therapy with omega-3 polyunsaturated fatty acids (PUFA). Recently, omega-3 PUFA via fish diet was reported to be linked to low incidence of AF. The main aim is to provide a cheap and safe preventative therapy against post-operative atrial fibrillation (AF), a key heart rhythm disorder that occurs in at least 1 in 4 patients after heart surgery and increases post-operative complications, limits recovery and increases hospital stay and cost. Biochemical study elements are important to gain valuable insight into the molecular mechanisms (directly in human heart) that underlie post-operative heart rhythm disorder and may delineate new more precise molecular targets for therapy. No previous clinical study has ever examined whether omega-3 PUFA therapy prevents post-operative heart rhythm disorder. Use of 3g-day omega-3 PUFA pre-treatment in the surgical setting has been shown to be safe in a number of small studies, including our own. Our preliminary data indicates that therapy increases heart and blood content of omega-3 PUFA ~2-fold, and reduces the incidence of AF. Post-operative AF is an expensive resource burden in all cardiothoracic surgery units of Australian hospitals and targets key health priorities. Due to the non-patentable nature of omega-3 PUFA, significant industry based support for clinical research is limited. A positive outcome would rapidly pave the way for widespread use in elective surgery. Reduced length of hospital stay, cost-savings, and the increase in productivity as healthy individuals return to their communities would nationally repay the investment many fold.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