Preconditioning: The Molecular Basis For Protection From Hepatic Ischemia-reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
When the blood supply to the liver is cut off temporarily (ischemia) and later restored (reperfusion) the liver is damaged by a process called ischemia-reperfusion (IR) injury. This is a major problem during liver surgery and is also an underlying problem in liver transplantation; following storage of a donor liver ready for placing into the recipient it can undergo a similar process called preservation injury. We now understand a lot about how IR comes about, particularly by the formation of da ....When the blood supply to the liver is cut off temporarily (ischemia) and later restored (reperfusion) the liver is damaged by a process called ischemia-reperfusion (IR) injury. This is a major problem during liver surgery and is also an underlying problem in liver transplantation; following storage of a donor liver ready for placing into the recipient it can undergo a similar process called preservation injury. We now understand a lot about how IR comes about, particularly by the formation of damaging oxygen radicals within liver cells to start a process of programmed cell death, but it remains difficult to prevent or treat IR injury. A recent breakthrough has been recognition that subjecting the liver to only a short period (5 or 10 minutes) of ischemia protects against a later period of prolonged ischemia or IR. In the investigator s mouse model, for example, such preconditioning was 60 to 90% protective (depending on the time after IR). This project seeks to understand how preconditioning works to protect the liver against IR injury. Our idea is that preconditioning generates a limited amount of oxygen radicals, and that these turn on signalling pathways in the cell that regulate certain protective genes. Genes that encode antioxidant and other anti-stress pathways are likely to be important, but so are genes that prepare the cell to enter the cell cycle and divide into new cells that regenerate the liver. Conversely, genes that program cell death may be turned off. The outcomes of this research will be to understand the molecular and cellular basis of how preconditioning protects against ischemia-reperfusion injury of the liver. This will allow drug treatments to be devised that, by simulating preconditioning, prevent this common and severe type of liver damage.Read moreRead less
Optimizing Implanted Cell Survival Using A Tissue Engineering Model
Funder
National Health and Medical Research Council
Funding Amount
$589,175.00
Summary
Cell therapy and tissue engineering involve the insertion of specific cells into damaged tissues or into a bioraector in a patient's body to generate new replacement tissues. This project seeks to improve two factors associated with inserting cells : 1. The innate survival characteristics of the cells being inserted, and 2. The blood vessel supply at the site of insertion. These techniques will greatly improve the survival of inserted cells.
Selective Therapies Targeting Tumour Vasculature Of Colorectal Liver Metastases
Funder
National Health and Medical Research Council
Funding Amount
$519,279.00
Summary
Cancer of the bowel is the second highest cause of cancer related deaths in Australia. Over 70% of these deaths are due to bowel cancer spread to the liver or liver metastases. Treatment options for the majority of patients with liver spread are limited. Although chemotherapies are a standard treatment option, they cause significant side-effects as they are small in size and thereby distributed to both cancer and normal tissue. Given the limitations of chemotherapy, our objective is to investiga ....Cancer of the bowel is the second highest cause of cancer related deaths in Australia. Over 70% of these deaths are due to bowel cancer spread to the liver or liver metastases. Treatment options for the majority of patients with liver spread are limited. Although chemotherapies are a standard treatment option, they cause significant side-effects as they are small in size and thereby distributed to both cancer and normal tissue. Given the limitations of chemotherapy, our objective is to investigate two new strategies which selectively destruct tumours with minimal effect to normal tissues. Cancer growth is dependent on an efficient blood supply. One strategy uses drug delivery systems (DDS) to selectively target cancers by exploiting the unique properties of tumour blood vessels. The second strategy uses vascular targeting agents (VTA's) which act on tumour vessels to reduce blood flow and starve the tumour of oxygen, leading to its destruction. We will be testing two agents: SMA-Pirarubicin, a DDS and an innovative VTA, Oxi4503, in an animal model of colorectal cancer liver metastases. Although these drugs are successful in destroying the majority of tumour cells, they have a patchy effect and do not completely destroy the cancerous growth. The varied effects of these agents may be due to variations in tissue hypoxia, tumour vessel structure or factors which trigger blood vessel formation and breakdown. These features will be investigated using techniques established within our laboratory. We will also investigate the combined effect of other novel agents and hyperbaric oxygen administration to improve the effectiveness of these drugs. A successful outcome will result in the development of an improved treatment method which targets tumours, producing maximum destruction with minimum side-effects. This has the potential to replace standard chemotherapies as the preferred treatment for patients with bowel cancer spread, with overall significant patient benefits.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