EGFR therapies for fatty liver surgery

描述（申请人提供）：肝脏手术切除可以治愈各种原发性和转移性肝脏肿瘤。脂肪肝手术与肝细胞增殖延迟和肝细胞坏死凋亡增加相关，导致肝功能衰竭、发病率和死亡率显著增加。迄今为止，脂肪肝手术后恢复缺陷的分子机制仍然知之甚少。目前还没有治疗方法可以预防肝衰竭或改善脂肪肝手术后的恢复。我们的长期目标是提高脂肪肝手术后的生存率，提高脂肪肝切除术的治愈率，扩大活体肝移植的供体池。这项特殊应用的目的是研究脂肪肝切除术后恢复的两个新的潜在治疗靶点，并将这些发现扩展到术前

DESCRIPTION (provided by applicant): Surgical liver resection can cure patients with a variety of primary and metastatic hepatic tumors. Surgery on fatty liver is associated with delayed hepatocyte proliferation and increased hepatocyte necroapoptosis, leading to a markedly increased rate of liver failure, morbidity and mortality. To date the molecular mechanisms responsible for defective recovery from liver surgery in the setting of fatty liver remain poorly understood. No therapies exist to prevent liver failure or improve recovery after fatty liver surgery. Our long-term goals are to improve survival after fatty liver surgery, to provde greater rates of curative fatty liver resections, and to expand the donor pool for living-donor livr transplantation. The objectives of this specific application are to investigate two new potential therapeutic target for fatty liver recovery after resection and to extend those findings into a pre clinical large animal model. Our studies show that fatty liver expresses reduced levels of EGFR, a critical mediator of hepatocyte proliferation and recovery of liver mass and function after injur. Acute resveratrol restores EGFR expression. Both genetic restoration of EGFR and resveratrol restores survival after fatty liver resection. Based on these data, our hypothesis is that reduced hepatocyte EGFR signaling leads directly to reduced survival and impaired recovery after hepatectomy. Rescue of survival after fatty liver surgery by resveratrol is mediated at least partly by EGFR up-regulation, but also likely through other pathways. To test this hypothesis, we will: 1) investigate the role of EGFR and define its key downstream signaling pathways in the hepatocyte response to fatty liver resection; 2) investigate the EGFR-dependent and independent mechanisms by which resveratrol rescues recovery from fatty liver surgery; and 3) establish the efficacy, tolerability and toxicity of resveratrol in an obese mini-pig model of fatt liver surgery. Once these studies are complete we will have defined the extent to which EGFR and downstream pathways can restore normal liver regeneration in fatty liver and completed preclinical studies to introduce resveratrol as a potential therapy.