HGF and Signaling Pathways in Hepatic Tissue Assembly

HGF 和肝组织组装中的信号通路

基本信息

批准号：
8462213
负责人：
GEORGE K MICHALOPOULOS
金额：
$ 27.66万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462213
关键词：
Acute Liver Failure Animals Apoptosis Apoptotic Automobile Driving Bile Acids Biliary Cell Death Cessation of life Clinical Epidermal Growth Factor Receptor Epithelial Cells ErbB Receptor Family Protein Event Failure Family Financial compensation Grant Hepatectomy Hepatic Tissue Hepatocyte Human Investigation Knowledge Lead Ligands Literature Liver Liver Failure Liver Regeneration Liver parenchyma Massive Hepatic Necrosis Mus Natural regeneration Necrosis Partial Hepatectomy Pathway interactions Prevention Proto-Oncogene Protein c-met Rattus Receptor Protein-Tyrosine Kinases Resected Role S Phase Scheme Serum-Free Culture Media Signal Pathway Signal Transduction System TNF gene TNFSF10 gene Therapeutic Therapeutic Intervention Transplantation Up-Regulation Ursidae Family base cytokine design hepatic necrosis human disease knock-down liver transplantation meetings member pro-apoptotic protein receptor receptor coupling regenerative research study transdifferentiation

项目摘要

PROJECT SUMMARY/ABSTRACT This is a revised renewal application for a grant, now in its 5th year, aiming to understand the role of HGF and signaling pathways in hepatic tissue assembly. Our recent studies have demonstrated that HGF and its receptor Met, as well as EGF receptor and the EGFR associated ligands) constitute the only two receptor tyrosine kinases capable of delivering a mitogenic signal to hepatocytes (in serum-free media and when administered to the whole animal, rat or mouse). We have also showed that HGF/Met and EGFR are the only two signaling systems capable of promoting transdifferentiation of hepatocytes to biliary epithelial cells in culture. These unique effects of HGF/Met and EGFR are highly significant. Many other receptor tyrosine kinases are expressed in hepatocytes and their ligands are capable of activating the cognate receptor, yet mitogenic signals are limited to HGF/Met and EGFR. We have recently applied short term knock down (KD) of either HGF/Met or EGFR by ShRNA and demonstrated that both have inhibitory effects on liver regeneration, that the one signal cannot compensate totally for the other, and that the effects are different in scope and complexity. KD of EGFR was followed by compensatory increases in other members of the ErbB family and upregulation of MET. In each instance, there was significant but not lethal activation of pro-apoptotic pathways. We further extend these studies in rats and performed a double KD of both HGF/Met and EGFR followed by partial hepatectomy (PHx). The result was complete liver failure, with massive apoptosis and necrosis of most hepatocytes and collapse of the hepatic parenchyma. This effect was not seen when double KD was performed without PHx. The proposed study will aim to determine the signals that lead to liver failure under the hypothesis that many cytokines involved in liver regeneration (e.g. TNF and TGFb1) can also function as agents that bring hepatocyte death and liver failure when the mitogenic signals of both EGFR and MET fail to function. In addition to the experimental studies, we will also analyze expression and status of activation of the above receptors as well cytokines capable of inducing hepatocyte death and liver failure in human liver material obtained from cases of fulminant hepatic necrosis.. Finally we will assess the importance of the compensatory mechanisms emerging after KD of EGFR and determine whether abrogation of these mechanisms is capable to also lead to liver failure by itself. The combination of these studies may allow us to understand the mechanisms that lead to massive hepatic necrosis as an aberrant dis-coordination of the early signals involved in liver regeneration and allow design of therapeutic interventions for prevention of massive hepatic necrosis based on rational mechanistic schemes.

项目概要/摘要这是修订后的拨款续展申请，现已进入第五年，旨在了解 HGF 的作用和肝组织组装中的信号通路。我们最近的研究表明，HGF 及其受体Met，以及EGF受体和EGFR相关配体）构成唯一的两种受体酪氨酸激酶能够向肝细胞传递促有丝分裂信号（在无血清培养基中以及当施用于整个动物、大鼠或小鼠）。我们还表明，HGF/Met 和 EGFR 是唯一两个信号系统能够促进肝细胞向胆道上皮细胞的转分化文化。 HGF/Met 和 EGFR 的这些独特作用非常显着。许多其他受体酪氨酸激酶在肝细胞中表达，其配体能够激活同源受体，但有丝分裂信号仅限于 HGF/Met 和 EGFR。我们最近应用了短期击倒（KD）通过 ShRNA 检测 HGF/Met 或 EGFR，并证明两者对肝再生都有抑制作用，一个信号不能完全补偿另一个信号，并且影响的范围和程度不同复杂。 EGFR KD 后，ErbB 家族其他成员代偿性增加，并且 MET 的上调。在每种情况下，促凋亡途径都有显着但非致命的激活。我们进一步在大鼠中扩展这些研究，并进行了 HGF/Met 和 EGFR 的双重 KD，然后部分肝切除术（PHx）。结果是完全肝衰竭，大多数细胞大量凋亡和坏死。肝细胞和肝实质塌陷。当双 KD 时，没有看到这种效果。无需 PHx 即可执行。拟议的研究旨在确定导致肝衰竭的信号假设许多参与肝再生的细胞因子（例如 TNF 和 TGFb1）也可以发挥作用当 EGFR 和 MET 的促有丝分裂信号未能发挥作用时，会导致肝细胞死亡和肝衰竭。功能。除了实验研究外，我们还将分析表达和激活状态上述受体以及能够诱导人肝脏肝细胞死亡和肝功能衰竭的细胞因子从暴发性肝坏死病例中获得的材料。最后我们将评估 EGFR KD 后出现的补偿机制，并确定是否废除这些机制机制本身也能够导致肝衰竭。这些研究的结合可能使我们能够了解导致大量肝坏死的机制，因为早期肝细胞的异常不协调参与肝再生的信号，并允许设计治疗干预措施以预防大规模肝损伤基于合理机制方案的肝坏死。