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EGFR therapies for fatty liver surgery

EGFR 疗法用于脂肪肝手术

基本信息

批准号：
8697048
负责人：
LEONIDAS G. KONIARIS
金额：
$ 33.93万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697048
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

项目摘要

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（申请人提供）：手术肝切除可以治愈多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性凋亡增加有关，导致肝衰竭发生率、发病率和死亡率显着增加。迄今为止，对于脂肪肝肝脏手术恢复不良的分子机制仍知之甚少。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，提高治愈性脂肪肝切除率，并扩大活体肝移植的供体库。这一具体应用的目的是研究切除后脂肪肝恢复的两个新的潜在治疗靶点，并将这些发现扩展到预治疗中。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 是肝细胞增殖以及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 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 信号传导减少直接导致肝切除术后生存率降低和恢复受损。白藜芦醇在脂肪肝手术后挽救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介导。为了检验这一假设，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依赖和独立机制； 3) 建立白藜芦醇在肥胖小型猪脂肪肝手术模型中的功效、耐受性和毒性。一旦这些研究完成，我们将确定 EGFR 和下游途径可以恢复脂肪肝正常肝再生的程度，并完成临床前研究，将白藜芦醇作为一种潜在的治疗方法。