Metabolic Engineering for Improved Liver Function

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DESCRIPTION (provided by applicant): Orthotopic liver transplantation (OLT) is a highly successful therapeutic modality for the treatment of both acute and chronic liver failure which is severely limited by the scarcity of donor livers. Among the livers donated after brain death, the most common single predisposing risk factor for postoperative liver failure is steatosis; thus, fatty livers are often considered to be "unacceptable" or "marginally acceptable" for transplantation. The incidence of hepatic steatosis is 10 to 25% based on autopsy studies and donor liver biopsies. It is clear that methods that would salvage discarded donors because of severe steatosis could significantly reduce the number of patient deaths, and help close the gap between supply and demand in liver transplantation. The overall hypothesis is that discarded donor livers, and more specifically steatotic livers (and in the long run donors after cardiac death), can be salvaged by perfusion with artificial solutions under well-controlled conditions and at physiological temperatures in order to promote defatting and cellular repair, and as a result made capable to withstand surgical procedures and reduce the risk of postoperative liver dysfunction to a level similar to that observed in normal livers. In the studies proposed herein, our objective is to apply this approach to fatty livers, and eventually to the more complex case of ischemic livers (i.e. from donors after cardiac death). Our specific aims are: (1) To optimize metabolism for defatting steatotic livers during normothermic or mild hypothermic perfusion; (2) To investigate the combined effects of heat shock and warm perfusion on microvascular function and transplantability in steatotic livers; (3) To develop a normothermic perfusion protocol that restores mitochondrial function and ATP stores in warm ischemic livers. In the short-term, the proposed studies could (a) provide the rationale basis for increasing the donor pool size; (b) improve the outcome of patients which receive marginal donor livers; (c) prolong the useful preservation time of steatotic, defatted, as well as warm ischemic livers. In the long-term, these studies will lead to (a) increased donor pool size and (b) increased organ storage time beyond the limits of current cold storage techniques. These outcomes will significantly alleviate donor shortage and lead the way to donor banking, with the potential to revolutionize donor liver allocation. PUBLIC HEALTH RELEVANCE: The proposed studies will provide basic scientific information and new technologies that will enable the recovery of donor livers that are otherwise rejected from the donor pool. In the long-term, these studies will lead to (a) increased donor pool size and (b) increased organ storage time beyond the limits of current cold storage techniques. These outcomes will significantly alleviate donor shortage and lead the way to donor banking, with the potential to revolutionize donor liver allocation.