HGF and Signaling Pathways in Hepatic Tissue Assembly

HGF 和肝组织组装中的信号通路

• 批准号: 6862635
• 负责人: GEORGE K MICHALOPOULOS
• 金额: $ 29.85万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862635
• 关键词: bile ducts; biological signal transduction; cell cell interaction; cell cycle; cell differentiation; cell proliferation; embryogenesis; epidermal growth factor; gene expression; genetically modified animals; hepatocellular carcinoma; hepatocyte growth factor; histogenesis; immunocytochemistry; implant; in situ hybridization; laboratory mouse; laboratory rat; liver; liver cells; liver regeneration; mitogens; tissue /cell culture

DESCRIPTION (provided by applicant): The purpose of this grant application is to explore new findings from our work as well as new models recently developed in our lab, in order to understand the mechanisms controlling assembly and formation of liver tissue. Gene array analysis of organoid cultures, composed of reassembled hepatic cellular elements, led to better understanding of the mechanisms by which dexamethasone, HGF and EGF regulate hepatic tissue assembly. We also found, unexpectedly, that in cultures maintained in the absence of dexamethasone HGF and EGF there is high proliferative activity, presumably driven by novel mitogen(s) not predicted from the literature derived from hepatocyte cultures or from whole animal, liver regeneration, models. The focused list of these potential mitogens identified from the gene array analysis will be studied in detail until the signaling molecules regulating this process are determined. After this is accomplished, the role of these mitogens in liver early embryogenesis, overall tissue repair and early carcinogenesis will be studied. We will also pursue further analysis of the role of HGF in liver embryology by utilizing an imported colony of Met -/+ mice, heterozygous for deletion of the HGF receptor (cMet). The livers of Met -/- embryos will be carried out alive further and beyond the day of embryonic lethality and will be studied as embryonic implants in the peritoneal cavity. We have recently developed this model and found out that it allows development and organization of all epithelial elements seen in mature liver including hepatocyte plates and bile ductules, even though mature portal triads do not appear. These studies will finally determine whether embryonic defects seen in livers of HGF -/- and Met -/- mice are primary to the genetic deletions or secondary to the placental anomalies seen in these embryos. The pathways leading to development of biliary ductules in wild type and Met -/- embryo livers after embryonic implantation will also allow determination of the importance of HGF as a key factor for biliary development, an item which has been often postulated but never proven. In addition to mitogenic signals, liver tissue assembly and repair also depends on the capacity of cellular elements to function as tissue restricted facultative stem cells for each other. Biliary cells can transdifferentiate to hepatocytes via the "oval cell" pathway. We have now shown that hepatocytes can transdifferentiate to biliary epithelium, in culture and in the whole animal. This relationship between hepatocytes and biliary epithelium establishes a new paradigm of organ stability in which mature, fully differentiated, cell types can function as "stem cells" for each other The signaling pathways and molecular determinants (growth and transcription factors) regulating this process will be studied in cultures, whole animals and embryonic implants. The above studies will provide insights and better understanding of the dynamics of liver tissue formation and provide paradigms with general applicability to other models of formation and maintenance of complex tissues.

描述（由申请人提供）：本赠款申请的目的是探索我们的工作中的新发现以及最近在实验室开发的新模型，以了解控制肝组织的组装和形成的机制。由重新组装的肝细胞元素组成的器官培养物的基因阵列分析，使对地塞米松，HGF和EGF调节肝组织组装的机制有了更好的了解。我们还意外地发现，在没有地塞米松HGF和EGF的情况下维持的培养物中存在很高的增殖活性，这可能是由新的有丝分裂原（S）驱动的，这是由源自肝细胞培养物或全部动物，肝脏再生，模型的文献所预测的。将详细研究从基因阵列分析中鉴定出的这些潜在有丝分析的重点列表，直到确定调节此过程的信号分子为止。完成此操作后，将研究这些有丝分裂原在肝脏早期胚胎发生，整体组织修复和早期致癌作用中的作用。我们还将通过利用Met - /+小鼠的进口菌落（杂合子）的杂合菌落来进一步分析HGF在肝脏胚胎学中的作用。 Met-/ - 胚胎的肝脏将在胚胎致死术的那天进一步及时进行，并将作为腹膜腔中的胚胎植入物进行研究。我们最近开发了该模型，并发现它允许在成熟肝脏中看到的所有上皮元素，包括肝细胞板和胆管，即使没有出现成熟的门户三合会。这些研究最终将确定在HGF - / - 和MET-/ - 小鼠肝脏中看到的胚胎缺陷是遗传缺失的主要或次要的胎盘异常。导致野生型和MET - / - 胚胎肝脏中胆汁螺旋杆发育的途径还将确定HGF作为胆道发育的关键因素的重要性，该项目经常被假设，但从未证实，但从未证实。除了有丝分裂信号外，肝组织组装和修复还取决于细胞元素相互限制组织限制性干细胞的能力。胆道细胞可以通过“椭圆形细胞”途径转差向肝细胞。现在，我们已经表明，肝细胞可以在培养物和整个动物中转变为胆道上皮。肝细胞与胆道上皮之间的这种关系建立了器官稳定性的新范式，其中成熟，完全分化的细胞类型可以互相起作用，以便在培养物，整个动物和胚胎植入物中研究这一过程的信号传导途径和分子确定性（生长和转录因子（生长和转录因子））。以上研究将提供洞察力和更好地理解肝组织形成的动力学，并为其他形成和维持复杂组织的模型提供一般适用性的范例。