EGFR therapies for fatty liver surgery

EGFR 疗法用于脂肪肝手术

• 批准号: 8345698
• 负责人: LEONIDAS G. KONIARIS
• 金额: $ 33.71万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8345698
• 关键词: Acute; Adult; Affect; American; Animal Model; Animals; Biochemical; Bioinformatics; Cells; Cessation of life; Clinical; Clinical Research; Collection; Data; Defect; Dose; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Excision; Family suidae; Fatty Liver; Functional disorder; Future; Gene Expression; Gene Transfer; Gene Transfer Techniques; Genes; Genetic; Goals; Growth; Hepatectomy; Hepatic; Hepatic Mass; Hepatocyte; Human; Incidence; Life; Liver; Liver Failure; Liver Regeneration; Liver diseases; Liver neoplasms; Living Donors; Measures; Mediating; Mediator of activation protein; Miniature Swine; Mitogens; Mitosis; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Obese Mice; Obesity; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pre-Clinical Model; Proteins; Proto-Oncogene Proteins c-akt; Receptor Signaling; Receptor Up-Regulation; Recovery; Regulation; Relative (related person); Reporting; Resveratrol; Role; STAT3 gene; STAT5A gene; Sampling; Scientist; Signal Pathway; Signal Transduction; Surgeon; Testing; Toxic effect; Transplant Surgeon; Transplantation; Work; base; drug discovery; effective therapy; improved; liver cell proliferation; liver function; liver transplantation; mortality; mouse model; multidisciplinary; novel; pre-clinical; preclinical study; prevent; receptor; receptor expression; regenerative; research clinical testing; response; restoration; therapeutic target; tumor

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. PUBLIC HEALTH RELEVANCE: Patients with fatty liver have much higher rates of illness and death after liver surgery. Using mouse and pig models, this pre-clinical study will examine two new potential therapies, EGFR and resveratrol, to improve outcomes after fatty liver surgery!

描述（由申请人提供）：手术肝切除术可以治愈各种原发性和转移性肝肿瘤患者。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，对脂肪肝患者肝脏手术后恢复不良的分子机制仍知之甚少。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，提高脂肪肝切除的治愈率，扩大活体肝移植的供体库。这项特殊应用的目的是研究两个新的潜在治疗靶点，用于脂肪肝切除术后的恢复，并将这些发现扩展到一个前 临床大型动物模型。我们的研究表明，脂肪肝表达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。急性白藜芦醇恢复EGFR表达。EGFR和白藜芦醇的基因恢复都能恢复脂肪肝切除术后的生存率。基于这些数据，我们的假设是，肝细胞EGFR信号转导减少直接导致肝切除术后生存率降低和恢复受损。白藜芦醇挽救脂肪肝手术后的生存至少部分是通过EGFR上调介导的，但也可能通过其他途径。为了验证这一假设，我们将：1）研究EGFR的作用，并定义其在肝细胞对脂肪肝切除反应中的关键下游信号通路; 2）研究白藜芦醇挽救脂肪肝手术恢复的EGFR依赖性和独立机制;和3）在脂肪肝手术的肥胖迷你猪模型中确定白藜芦醇的功效、耐受性和毒性。一旦这些研究完成，我们将确定EGFR和下游途径在多大程度上可以恢复脂肪肝的正常肝再生，并完成临床前研究，以引入白藜芦醇作为潜在的治疗方法。 公共卫生相关性：脂肪肝患者在肝脏手术后的患病率和死亡率更高。使用小鼠和猪模型，这项临床前研究将研究两种新的潜在疗法，EGFR和白藜芦醇，以改善脂肪肝手术后的结果！