HGF IN LIVER REGENERATION, DIFFERENTIATION AND NEOPLASIA

HGF 在肝脏再生、分化和肿瘤中的作用

• 批准号: 2856240
• 负责人: GEORGE K MICHALOPOULOS
• 金额: $ 25.93万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-15 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856240
• 关键词: cell growth regulation; embryo /fetus tissue /cell culture; genetically modified animals; growth factor receptors; hepatocellular carcinoma; hepatocyte growth factor; histogenesis; laboratory mouse; laboratory rat; liver cells; liver neoplasms; liver regeneration; mitogens; molecular oncology; neoplastic cell; phenotype; tissue /cell culture; transcription factor; tumor promoters

Hepatocyte Growth Factor is a multifunctional cytokine with mitogenic motogenic and morphogenic effects on many organs and cell types. Liver, however, is the organ whose development is predominantly affected in mice with gene knockouts for either HGF or its receptor (Met). In addition, HGF levels rise in the plasma during liver regeneration but not in that of other organs. The main aim of this application is to determine his HGF essential for liver regeneration and embryonic development and how is it brought to where it is needed by release from matrix, new synthesis and activation. We will examine the pathways leading to HGF release from liver after PHx. Evidence is presented that an orchestrated cascade of events starting from the urokinase receptor (uPAR) leads to simultaneous matrix degradation and HGF release and activation. Chronology of receptor activation following partial hepatectomy suggests that activation of other receptors precedes activation of Met. We will focus on the immediate early extracellular events that trigger the subsequent cascade of events leading to regeneration. We will use a newly developed in our lab culture system where parenchymal hepatocytes can expand as undifferentiated clones and undergo phenotypic transition to either mature hepatocytes or ductular hepatocytes. In these cultures of hepatoblasts, HGF induces the ductular phenotype. Ductular transformation of hepatocytes occurs transiently during embryology and during the late stages of fulminant hepatitis. Based on our findings will explore the hypothesis that formation of the ductular hepatocyte phenotype is under control of HGF and may correlate with the appearance of new transcription factors. Given the critical dependence of embryonic liver on this ductular transformation as well as the impact of the ductular transformation of hepatocytes to the lethality of fulminant hepatitis, these studies will examine the role of HGF in two critical stages at the beginning and (sometimes) the end of life. The role of HGF in hepatic neoplasia remains puzzling. Exogenously administered HGF inhibits proliferation of early hepatocellular carcinomas. Neoplastic development in HGF transgenics targeted to liver is far less than TGFalpha. We show that forced expression of HGF may accelerate growth in hepatoblasts. We will study growth and differentiation properties in culture and in transplantation of hepatoblasts /hepatocytes with forced expression of HGF. Following recent results in our lab, we will also pursue studies to examine the possibility that the effect of exogenous HGF on hepatic neoplasia may be stimulatory or inhibitory based on aberrant phosphorylation of Met induced by insulin or transferrin receptors.

肝细胞生长因子是一种多功能促有丝分裂因子 对许多器官和细胞类型的运动和形态发生的影响。肝脏， 然而，发育主要受影响的器官是小鼠吗？ HGF或其受体(Met)的基因敲除。此外，HGF 在肝脏再生过程中，血浆中的水平升高，但在肝再生过程中不会 其他器官。此应用程序的主要目的是确定其HGF 对肝脏再生和胚胎发育是必不可少的，它是如何 通过从基质中释放、新的合成和 激活。我们将研究导致HGF从肝脏释放的途径。 在PHX之后。有证据表明，一系列精心策划的事件 从尿激酶受体(UPAR)开始导致同时基质 降解和肝细胞生长因子的释放和激活。受体年表 肝部分切除后的激活提示其他 受体先于甲硫氨酸的激活。我们将专注于即刻的早期 触发后续事件级联的细胞外事件 为再生干杯。我们将在实验室中使用一种新开发的培养系统 其中实质肝细胞可以作为未分化的克隆和 经历表型向成熟肝细胞或导管的转变 肝细胞。在这些培养的肝母细胞中，HGF诱导导管 表型。肝细胞发生一过性的导管转化 胚胎学和重型肝炎晚期。基于我们的 这些发现将探索这样一种假设，即胆管的形成 肝细胞表型受HGF控制，可能与 新的转录因子的出现。鉴于……的严重依赖 胚胎肝脏对这种胆管转化的影响以及 肝细胞向暴发性致死的导管转化 这些研究将考察HGF在两个关键的肝炎中的作用 生命的开始阶段和(有时)结束阶段。肝细胞生长因子的作用 肝肿瘤的发病情况仍然令人费解。外源性应用HGF 抑制早期肝细胞癌的增殖。肿瘤 针对肝脏的肝细胞生长因子转基因研究的进展远远低于转化生长因子α。 我们发现，强制表达HGF可能会加速血管内皮细胞的生长 肝母细胞。我们将研究生长和分化特性 肝母细胞/肝细胞的培养和移植 肝细胞生长因子的表达。根据我们实验室的最新结果，我们还将继续 研究探讨外源性HGF对血管紧张素转换酶活性的影响 基于异常，肝肿瘤可以是刺激的或抑制的 胰岛素或转铁蛋白受体诱导蛋氨酸的磷酸化。