HGF and Signaling Pathways in Hepatic Tissue Assembly

HGF 和肝组织组装中的信号通路

• 批准号: 8259209
• 负责人: GEORGE K MICHALOPOULOS
• 金额: $ 29.42万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8259209
• 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

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.

项目摘要/摘要 这是一份修订后的拨款续期申请，现已进入第五个年头，旨在了解HGF和 肝组织组装中的信号通路。我们最近的研究表明，HGF及其 Met受体以及EGF受体和EGFR相关配体)构成了仅有的两种受体 能够向肝细胞传递有丝分裂信号的酪氨酸激酶(在无血清介质中和在 给整个动物、大鼠或小鼠注射)。我们还表明，HGF/Met和EGFR是唯一 促进肝细胞转分化为胆管上皮细胞的两种信号系统 文化。HGF/Met和EGFR的这些独特作用是非常显著的。许多其他受体酪氨酸 激酶在肝细胞中表达，它们的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穿(KD) HGF/Met或EGFR通过shRNA表达，证明两者都有抑制肝再生的作用。 一个信号不能完全补偿另一个信号，而且影响的范围和范围是不同的 复杂性。在EGFR的KD之后，ErbB家族的其他成员的补偿性增加和 MET的上调。在每一种情况下，促凋亡通路都有显著的激活，但不是致命的。 我们在大鼠身上进一步扩展了这些研究，并进行了HGF/Met和EGFR的双重KD，随后 肝部分切除术(PHX)。结果是完全肝功能衰竭，大部分细胞出现大量的细胞凋亡和坏死。 肝细胞和肝实质塌陷。这种影响在双KD时未见 在不使用PHX的情况下执行。这项拟议的研究旨在确定导致肝功能衰竭的信号 假设许多参与肝再生的细胞因子(例如，肿瘤坏死因子和肿瘤生长因子b1)也可以发挥作用 当EGFR和MET的有丝分裂信号均失败时，导致肝细胞死亡和肝功能衰竭的药物 功能。除了实验研究外，我们还将分析该基因的表达和激活状态 上述受体以及可诱导人肝细胞死亡和肝功能衰竭的细胞因子 材料取自暴发性肝坏死病例..最后，我们将评估 EGFR KD后出现的代偿机制及其是否被取消 这些机制本身也可能导致肝功能衰竭。这些研究的结合可能使我们能够 将导致大量肝坏死的机制理解为早期的异常失调 参与肝脏再生的信号，并允许设计治疗干预措施，以防止大量 以合理的机制方案为基础的肝坏死。