EGFR therapies for fatty liver surgery

描述(申请人提供)：外科肝切除术可以治愈各种原发和转移性肝肿瘤患者。脂肪肝手术后肝细胞增殖延迟，肝细胞坏死增加，导致肝功能衰竭发生率、发病率和死亡率显著增加。到目前为止，脂肪肝患者肝脏手术后缺陷恢复的分子机制仍然知之甚少。目前还没有预防肝功能衰竭或改善脂肪肝手术后恢复的治疗方法。我们的长期目标是提高脂肪肝手术后的存活率，提高根治性脂肪肝切除率，并扩大活体供肝移植的供体来源。这一具体应用目的是研究两个新的用于脂肪肝切除后恢复的潜在治疗靶点，并将这些发现扩展到前 临床大动物模型。我们的研究表明，脂肪肝表达的EGFR水平降低，EGFR是肝细胞增殖和损伤后肝脏质量和功能恢复的关键介质。急性白藜芦醇可恢复EGFR的表达。EGFR和白藜芦醇的基因修复均可恢复脂肪肝切除后的存活率。基于这些数据，我们的假设是，肝细胞EGFR信号的减少直接导致肝切除术后存活率的降低和恢复的损害。白藜芦醇对脂肪肝手术后存活率的挽救至少部分是通过上调EGFR介导的，但也可能通过其他途径。为了验证这一假说，我们将：1)研究EGFR在脂肪肝切除后肝细胞反应中的作用并确定其关键的下游信号通路；2)研究白藜芦醇拯救脂肪肝手术后恢复的EGFR依赖和独立机制；3)在肥胖症小型猪脂肪肝手术模型中建立白藜芦醇的疗效、耐受性和毒性。一旦这些研究完成，我们将确定EGFR和下游通路可以在多大程度上恢复脂肪肝患者的正常肝再生，并完成临床前研究，引入白藜芦醇作为一种潜在的治疗方法。

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.