EGFR therapies for fatty liver surgery

EGFR 疗法用于脂肪肝手术

• 批准号: 8535753
• 负责人: LEONIDAS G. KONIARIS
• 金额: --
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535753
• 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.

描述（由申请人提供）：手术肝切除可以治愈患有多种原发性和转移性肝肿瘤的患者。脂肪肝手术与延迟的肝细胞增殖和增加的肝细胞坏死性有关，导致肝衰竭，发病率和死亡率显着增加。迄今为止，在脂肪肝的情况下，导致从肝脏手术中恢复有缺陷的分子机制仍然了解不足。没有疗法可以防止肝肝手术后肝衰竭或改善康复。我们的长期目标是改善脂肪肝手术后的生存，以提高治疗性脂肪肝切除率，并扩大供体池以进行活含量的LIVR移植。该特定应用的目标是研究切除后脂肪肝恢复的两个新的潜在治疗靶标，并将这些发现扩展到PRE 临床大动物模型。我们的研究表明，脂肪肝表示降低的EGFR水平，EGFR是肝细胞增殖的关键介体，肝脏质量和损伤后功能的恢复。急性白藜芦醇恢复EGFR表达。 EGFR的遗传恢复和白藜芦醇均可以恢复脂肪肝切除后的生存。基于这些数据，我们的假设是减少的肝细胞EGFR信号直接导致肝切除术后的存活率和恢复受损。白藜芦醇至少部分通过EGFR上调来介导脂肪肝手术后的生存率，但也可能通过其他途径介导。为了检验这一假设，我们将：1）研究EGFR的作用，并在肝细胞对脂肪肝切除术中定义其下游信号通路； 2）研究白藜芦醇从脂肪肝手术中恢复的EGFR依赖性和独立机制； 3）建立白藜芦醇在肥胖的Fatt肝手术模型中的功效，耐受性和毒性。这些研究完成后，我们将定义EGFR和下游途径可以在多大程度上恢复脂肪肝中的正常肝脏再生，并完成临床前研究以引入白藜芦醇作为潜在的治疗。