PROJECT SUMMARY/ABSTRACT Thousands patients with end-staged liver failure die every year world-wide due to the lack of donor livers. Our long-term goal is to improve the usage of the livers from older donors to ameliorate the shortage of donor livers. Toward this goal, we have found that by treating old mice with ?-aminobutyric acid (GABA) protocol, we can restore the regenerative capability in the livers of 24-month old mice, the equivalent of 70-year old humans. Based on these results, we hypothesized that old hepatocytes, once reactivated by GABA, can readily regenerate in response to a mitogenic stimulus. We will test our hypothesis in the following specific aims: (1) Identify that hepatocytes in the livers of GABA-treated aged mice readily regenerate within 6 h to 8 h in addition to the improved regeneration at the usual 36 h following mitogenic stimulus; (2) Identify GABA-A and -B receptors and their individual roles in hepatocellular reactivation providing impetus for hepatocyte regeneration in livers of aged mice; we will use selective agonists and antagonists and hepatocellular specific genetic deletion of each receptor type in delineating the role and contribution of the receptors to liver regeneration in aged mice; (3) To corroborate that the unused livers from human donors, after being treated with GABA, will have augmented ability to regenerate upon mitogenic stimulus. The rationale for the proposed research is to understand the mechanisms by which GABA makes old hepatocytes functionally young again which will provide a mechanism-based foundation of safety and usefulness of GABA as we translate this knowledge clinically to make aged livers becoming usable donor livers. The results from the proposed work will improve the liver-related health and will effectively expand donor pool for transplantation.