Therapeutic strategies to improve function of high risk liver grafts

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PROJECT SUMMARY This proposal presents a five-year research career development program focused scientifically on improving the viability of liver grafts from extended criteria donors (ECD) for transplantation. The candidate is currently an Assistant Professor of Surgery at Duke University. The candidate has previous research and clinical experience in transplant surgery involving normothermic machine perfusion (NMP), whereby an organ is housed in an ex vivo environment and perfused with nutrients and oxygen under physiologic conditions. The candidate will now advance this technology by using NMP to deliver novel therapeutics to transplant grafts, and focus his research on mitochondrial contributions to graft dysfunction. The candidate has assembled a diverse mentoring committee of investigators with expertise in transplant surgery, NMP, molecular therapeutics, and mitochondrial biology. The proposed training and experiments will provide the candidate with a combined skillset in innate immunity, mitochondrial biology, transplant surgery, and biostatistics that will enable him transition to research independence as a surgeon-scientist dedicated to reducing the organ shortage in the field of transplant surgery. The primary obstacle facing the field of liver transplantation is the severe shortage of donor organs. In 2018, 8,000 liver transplants were performed in the United States, but another 13,000 patients remain on the waitlist. The mortality rate of patients on the waitlist is exceedingly high, at over 20% per year. One strategy with great potential to increase organ availability is utilization of extended criteria donors (ECDs). The ECD designation includes donors of advanced age (≥ 60 years), those with significant hepatic steatosis, and livers donated after cardiac death. However, widespread use of ECD livers has been limited by several factors, including increased rates of graft dysfunction, graft failure, and recipient death. These poor outcomes have been attributed to a reduced capacity of ECD livers to recover from ischemia-reperfusion (I-R) injury. I-R injury induces mitochondrial dysfunction in the graft that leads to cell death. The dying cells in the graft release a broad array of molecules known collectively as damage-associated molecular patterns (DAMPs), which are known to activate inflammatory and cell death pathways, leading to further graft injury. We hypothesize that reducing the damage caused by mitochondrial dysfunction and DAMPs will improve the viability of ECD livers for transplant and reduce the current shortage of livers available for transplantation. The use of NMP technology provides an ideal platform for delivering therapeutics to improve ECD graft function. This project will employ NMP technology to deliver therapeutics that enhance mitochondrial function and removing harmful DAMPs using our novel DAMP-capturing membrane. The aims of this proposal are: 1) determine the effects of enhanced mitochondrial function on ECD liver transplantation, 2) determine the effects of removing DAMPs on post-transplant graft injury and function.