HGF and Signaling Pathways in Hepatic Tissue Assembly

HGF 和肝组织组装中的信号通路

• 批准号: 7196476
• 负责人: GEORGE K MICHALOPOULOS
• 金额: $ 28.3万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196476
• 关键词: Address; Adult; Affect; Animals; Appendix; Applications Grants; Biliary; Cells; Cessation of life; Complex; Cultured Cells; Defect; Development; Dexamethasone; EGF gene; Elements; Embryo; Embryology; Embryonic Development; Epidermal Growth Factor Receptor; Epithelial; Epithelium; Exhibits; Female; Gene Expression; Genes; Genetic; Greater sac of peritoneum; Growth; Hepatic; Hepatic Tissue; Hepatocyte; Histologic; Histology; Implant; In Situ; In Vitro; Interleukin-6; Ligands; Literature; Liver; Liver Regeneration; Liver neoplasms; Maintenance; Mitogens; Modeling; Molecular; Mus; Organ; Organoids; Partial Hepatectomy; Pathway interactions; Pattern; Peritoneal; Portal triad; Primary carcinoma of the liver cells; Primordium; Process; Proto-Oncogene Protein c-met; Purpose; Rate; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Standards of Weights and Measures; Stem cells; Testing; Tissue Model; Tissues; Work; Wound Healing; bile duct; biliary tract; carcinogenesis; cell type; computerized data processing; day; extracellular; implantation; in vivo; insight; methionylmethionine; novel; oval cell; receptor; repaired; size; tool; transcription factor

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）：本资助申请的目的是探索我们工作的新发现以及我们实验室最近开发的新模型，以了解控制肝组织组装和形成的机制。对重组肝细胞元件组成的类器官培养物进行基因阵列分析，有助于更好地了解地塞米松、HGF和EGF调节肝组织组装的机制。我们还意外地发现，在缺乏地塞米松HGF和EGF的培养中，存在高增殖活性，可能是由未从肝细胞培养或全动物肝再生模型中得到的文献中预测的新型有丝分裂原驱动的。从基因阵列分析中鉴定出的这些潜在有丝分裂原的重点列表将被详细研究，直到确定调节这一过程的信号分子。研究完成后，将进一步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癌变中的作用。我们还将进一步分析HGF在肝胚胎学中的作用，利用进口的Met -/+小鼠集落，杂合缺失HGF受体（cMet）。Met -/-胚胎的肝脏将在胚胎死亡日之后继续活取，并将作为胚胎植入腹腔进行研究。我们最近开发了这个模型，并发现它允许成熟肝脏中所有上皮元素的发育和组织，包括肝细胞板和胆管，即使没有出现成熟的门静脉三联体。这些研究将最终确定在HGF -/-和Met -/-小鼠肝脏中观察到的胚胎缺陷是由基因缺失引起的，还是由胚胎中观察到的胎盘异常引起的。野生型和Met -/-胚胎肝在胚胎着床后导致胆管发育的途径也将允许确定HGF作为胆道发育的关键因素的重要性，这一项经常被假设但从未被证实。除了有丝分裂信号外，肝组织组装和修复还依赖于细胞元件作为组织限制性兼性干细胞相互作用的能力。胆道细胞可通过“卵圆细胞”途径向肝细胞转分化。我们现在已经证明，在培养和整个动物中，肝细胞可以转分化为胆道上皮。肝细胞和胆道上皮之间的这种关系建立了一种器官稳定性的新模式，在这种模式中，成熟的、完全分化的细胞类型可以相互充当“干细胞”。调节这一过程的信号通路和分子决定因素（生长和转录因子）将在培养物、全动物和胚胎植入物中进行研究。上述研究将提供对肝组织形成动力学的见解和更好的理解，并为复杂组织形成和维持的其他模型提供具有普遍适用性的范例。