Assessment Of Hypoxia And Hepatic Metabolism In Cirrhotic Rats Using NMR
Funder
National Health and Medical Research Council
Funding Amount
$355,341.00
Summary
Liver function and hepatic drug metabolism are impaired in patients with cirrhosis but there is currently no adequate explanation to account for this. As a direct consequence, there is no useful therapy beyond liver transplantation. We propose studies aimed at confirming a hypothesis on the mechanisms underlying the development of cirrhosis. From this mechanistic hypothesis, a testable therapeutic hypothesis has been derived. Our primary mechanistic hypothesis is that cirrhosis is associated wit ....Liver function and hepatic drug metabolism are impaired in patients with cirrhosis but there is currently no adequate explanation to account for this. As a direct consequence, there is no useful therapy beyond liver transplantation. We propose studies aimed at confirming a hypothesis on the mechanisms underlying the development of cirrhosis. From this mechanistic hypothesis, a testable therapeutic hypothesis has been derived. Our primary mechanistic hypothesis is that cirrhosis is associated with reduced oxygen delivery from the blood supply into the liver due to a process known as capillarisation (i.e., The Oxygen Limitation Theory). It is proposed that this reduced oxygen availability leads to impairment of liver function. The major aim of this research project is to confirm or refute the presence of intracellular hypoxia (i.e., decreased oxygen in cells) using nuclear magnetic resonance (NMR) techniques and cirrhotic rats. The nature of any metabolic disturbances or changes in cellular components resulting from intracellular hypoxia will then be characterised. The project will also aim to confirm the impairment of oxygen-dependent drug metabolism in cirrhosis by using NMR to measure the degradation or elimination of a fluorinated drug. Our hypothesis for therapy is that intracellular hypoxia may be reversed, and global liver function improved, by oxygen supplementation and-or an increase in hepatic arterial flow by using oral hepatic arterial vasodilators. Vasodilators exert their action by direct relaxation of blood vessels or by blocking the action of vasoconstrictors. Vasodilators that act solely on the hepatic artery and their influence upon blood pressure will be studied using treated rat livers so that such vasodilators can be tested for their ability to modify liver function in cirrhotic rats in vivo. The ultimate goal will be to carry these observations into studies in normal healthy volunteers and cirrhotic patients in the future.Read moreRead less
Improving Kidney Transplant Outcomes Using Normothermic Machine Perfusion
Funder
National Health and Medical Research Council
Funding Amount
$778,232.00
Summary
Kidneys donated for transplantation are at risk of damage that prevent the organ from working and reduce its lifespan. Normothermic machine perfusion is a device that can circulate oxygenated blood at normal body temperature through a donor kidney prior to transplantation. In doing so it is able to resuscitate the kidney and prevent injury. We will determine how machine perfusion achieves this remarkable effect and investigate new treatments for kidney injury.